International Journal of

Molecular Sciences

Review
Autophagy as a Target for Non-Immune Intrinsic Functions of
Programmed Cell Death-Ligand 1 in Cancer
Blanca Estela García-Pérez 1, * , Christian Pérez-Torres 1 , Shantal Lizbeth Baltierra-Uribe 1 , Juan Castillo-Cruz 1,2
and Nayeli Shantal Castrejón-Jiménez 3

1 Departmento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional,

Prolongación de Carpio y Plan de Ayala S/N, Col. Santo Tomás, Alcaldía Miguel Hidalgo,
Mexico City 11340, Mexico
2 Departmento de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional,
Prolongación de Carpio y Plan de Ayala S/N, Col. Santo Tomás, Alcaldía Miguel Hidalgo,
Mexico City 11340, Mexico
3 Área Académica de Medicina Veterinaria y Zootecnia, Instituto de Ciencias Agropecuarias, Universidad
Autónoma del Estado de Hidalgo, Av. Universidad km. 1. Exhacienda de Aquetzalpa A.P. 32,
Tulancingo 43600, Mexico
* Correspondence: [email protected]; Tel.: +52-5557296300 (ext. 46209)

Abstract: Autophagy is a catabolic process that is essential to the maintenance of homeostasis through
the cellular recycling of damaged organelles or misfolded proteins, which sustains energy balance.
Additionally, autophagy plays a dual role in modulating the development and progression of cancer
and inducing a survival strategy in tumoral cells. Programmed cell death-ligand 1 (PD-L1) modulates
the immune response and is responsible for maintaining self-tolerance. Because tumor cells exploit
the PD-L1–PD-1 interaction to subvert the immune response, immunotherapy has been developed
based on the use of PD-L1-blocking antibodies. Recent evidence has suggested a bidirectional
regulation between autophagy and PD-L1 molecule expression in tumor cells. Moreover, the research
into the intrinsic properties of PD-L1 has highlighted new functions that are advantageous to tumor
cells. The relationship between autophagy and PD-L1 is complex and still not fully understood;
Citation: García-Pérez, B.E.; its effects can be context-dependent and might differ between tumoral cells. This review refines
Pérez-Torres, C.; Baltierra-Uribe, S.L.; our understanding of the non-immune intrinsic functions of PD-L1 and its potential influence on
Castillo-Cruz, J.; Castrejón-Jiménez, autophagy, how these could allow the survival of tumor cells, and what this means for the efficacy of
N.S. Autophagy as a Target for anti-PD-L1 therapeutic strategies.
Non-Immune Intrinsic Functions of
Programmed Cell Death-Ligand 1 in Keywords: PD-L1; autophagy; mTOR; cancer; immunotherapy
Cancer. Int. J. Mol. Sci. 2023, 24,
15016. https://doi.org/10.3390/
ijms241915016

Academic Editor: Ming-Ju Hsieh 1. Introduction

Received: 7 September 2023
Autophagy is a complex and dynamic recycling system responsible for the removal
Revised: 27 September 2023 of senescent or malfunctioning organelles. The cytoplasmic material sequestered via au-
Accepted: 7 October 2023 tophagy is delivered to lysosomes for degradation, allowing for its eventual reutilization.
Published: 9 October 2023 In recent years, it has been shown that this process is a relevant topic for researchers, as
alterations in autophagy have been implicated in various infectious diseases, neurodegen-
erative diseases, metabolic diseases, and cancers, among other conditions [1–3]. In many
diseases, autophagy seems to play a dual role; for this reason, its manipulation as a form of
Copyright: © 2023 by the authors.
therapy continues to be controversial. As a catabolic pathway, autophagy maintains the
Licensee MDPI, Basel, Switzerland.
quality control of cells. This homeostatic process removes damaged organelles, misfolded
This article is an open access article
proteins, and microorganisms; additionally, it helps preserve the cell during starvation and
distributed under the terms and
oxidative stress [4]. These elements are degraded and recycled via the lysosome-dependent
conditions of the Creative Commons
pathway. Paradoxically, this homeostatic cellular pathway plays a dual role in cancer; this
Attribution (CC BY) license (https://
role depends on the stage of cancer development, nutrient accessibility, microenvironmen-
creativecommons.org/licenses/by/
4.0/).
tal stress, pathogenic conditions, and the immune response [5]. It has been demonstrated

Int. J. Mol. Sci. 2023, 24, 15016. https://doi.org/10.3390/ijms241915016 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2023, 24, 15016 2 of 19

that autophagy suppresses chronic tissue damage, preventing tumor initiation, especially in
the early stages of tumorigenesis. Moreover, autophagy contributes to the maintenance of
genomic stability, the suppression of oxidative stress, and the inhibition of NRF2 activation,
and it also plays a protective role by suppressing metastasis [6,7]. Different studies have
demonstrated that the molecules involved in autophagy are the key to suppressing tumors.
Beclin-1 is a protein that is involved in the early stages of autophagy and has been associ-
ated with being a tumor suppressor. Beclin-1 overexpression has been shown to suppress
the progression of gastric cancer by promoting apoptosis and reducing cell migration [8].
Moreover, it is known that Beclin-1−/− mutant mice die early in embryogenesis, and
Beclin-1+/− mutant mice suffer from a high incidence of spontaneous tumors [9]. Wijshake
and colleagues found that Beclin-1 promotes the localization of E-cadherin on plasma mem-
branes. Thus, Beclin-1, as a breast-tumor-suppressor molecule, restricts tumor growth and
metastases when E-cadherin is present at the cell surface [10]. Another group of proteins
involved in the autophagy process in relation to the inhibition of cancer progression are
autophagy-related proteins (ATGs), which are involved in membrane dynamics during
autophagy [11,12]. ATG proteins are responsible for orchestrating the autophagic process,
which allows for the elimination of damaged proteins and organelles, cellular stress, and
aging. A study showed that mice with a systemic mosaic deletion of ATG5 developed
multiple benign adenomas only in the liver; the analysis of hepatic cells demonstrated
the presence of abnormally enlarged mitochondria, the accumulation of reactive oxygen
species, and genomic damage. Through an analysis of ubiquitin-positive aggregates and
a higher accumulation of p62 (a selective substrate of autophagy), the authors confirmed
the role of defective autophagy in the development of tumors. Moreover, they extended
their study of this topic in a model of liver-specific ATG7-deficient mice, which confirmed
that tumor progression was partially suppressed via p62 deletion [13]. This evidence
emphasizes the role of autophagy and its related proteins as tumor-suppressing factors.
Regarding the other approach to autophagy in cancer cells, several studies have demon-
strated that the autophagy pathway supplies tumor cells with nutrients [14,15], increases
the survival of cancer cells and their resistance to stress factors [16], lowers p53 levels [17],
favors tumor metabolism [18,19], inhibits the surface expression of MHC-I on cancer cells,
protecting them from lymphocyte cytotoxicity [20], and promotes metastasis [21]. Moreover,
an association between autophagy and programmed cell death-ligand 1 (PD-L1) expression
has recently emerged. This relationship has captured the attention of researchers because
the abnormally high expression of PD-L1 in tumor cells and antigen-presenting cells medi-
ates the immune evasion of tumors. In physiological conditions, PD-L1 is a molecule that
intricately regulates the immune response triggered by T lymphocytes based on recognition
by PD-1 and plays an important role in the maintenance of self-tolerance [22]. Since the
first description of immune checkpoint molecules, intensive research has been conducted,
mainly because cancer cells take advantage of these molecules to deactivate the effector
functions of lymphocytes and then escape immune surveillance [23]. Thus, in recent years,
the PD-1–PD-L1 axis has been extensively researched in the context of cancer, because it
is a promising therapeutic target. With the understanding of the immunological context
of these checkpoint molecules, several monoclonal antibodies that block them have been
developed (such as nivolumab, pembrolizumab, and pidilizumab, among others) and have
demonstrated antitumor activity in a number of tumor types [24–27]. Unfortunately, not
all types of cancer have been associated with a clinical response, emphasizing the need
for a better understanding of these molecules that considers their signaling and regulation
mechanisms. The upregulation of PD-L1 in cancer cells has been addressed in detail in
numerous reviews [28–31]. Most of these reviews highlight genomic alterations, epigenetic
modifications, oncogenic signaling, inflammatory signaling, transcriptional regulation, and
post-transcriptional and post-translational modifications as mechanisms responsible for
PD-L1 regulation. Recently, autophagy has been highlighted as another PD-L1 regulation
mechanism [32–34].
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 3 of 19

Int. J. Mol. Sci. 2023, 24, 15016 3 of 19

modifications as mechanisms responsible for PD-L1 regulation. Recently, autophagy has
been highlighted as another PD-L1 regulation mechanism [32–34].
Structurally, PD-L1 is a type I transmembrane glycoprotein that belongs to the B7
family.Structurally, PD-L1 is a type
It is a 290-amino-acid I transmembrane
protein receptor encoded glycoprotein
by the CD274that belongs to the on
gene, located B7
family. It is a 290-amino-acid protein receptor encoded by the
chromosome 9 in humans, and its sequence is highly conserved [35,36]. It contains IgV CD274 gene, located on
chromosome 9 in humans, and its sequence is highly conserved [35,36]. It contains IgV and
and IgC structure domains, a hydrophobic transmembrane domain, and a short (30 aa)
IgC structure domains, a hydrophobic transmembrane domain, and a short (30 aa) cyto-
cytoplasmic tail structure domain (Figure 1) that does not contain canonical signal motifs
plasmic tail structure domain (Figure 1) that does not contain canonical signal motifs [36].
[36]. To date, the functionality of the cytoplasmic tail remains unclear. It is clear that the
To date, the functionality of the cytoplasmic tail remains unclear. It is clear that the main
main studies on the PD-L1 molecule have focused on the context of its interaction with
studies on the PD-L1 molecule have focused on the context of its interaction with PD-1 and
PD-1 and its inhibitory effect on the T-cell response. However, recent works have high-
its inhibitory effect on the T-cell response. However, recent works have highlighted that
lighted that PD-L1 can regulate tumor-intrinsic signals related to cell growth and survival,
PD-L1 can regulate tumor-intrinsic signals related to cell growth and survival, and early
and early attempts have been made to establish the role of the intracytoplasmic domain
attempts have been made to establish the role of the intracytoplasmic domain of PD-L1 in
of PD-L1 in mediating the transduction of non-canonical intracellular signals [37]. The
mediating the transduction of non-canonical intracellular signals [37]. The interconnection
interconnection between PD-L1 and autophagy has been documented in some reviews.
between PD-L1 and autophagy has been documented in some reviews. Robainas and
Robainas and colleagues summarized and discussed the studies related to the use of im-
colleagues summarized and discussed the studies related to the use of immune checkpoint
mune checkpoint
inhibitors inhibitors
in combination in autophagy
with combination with autophagy
inhibitors inhibitors
as a synergic strategyastoa synergic strat-
prevent tumor
egy to preventCui
progression. tumor
et al.progression. Cui et al.the
mainly highlighted mainly highlighted
mechanisms the mechanisms
involved involved
in the regulation of
in
PD-L1 via autophagy; similarly, Gao and Chen discussed the ongoing investigationongoing
the regulation of PD-L1 via autophagy; similarly, Gao and Chen discussed the into the
investigation
mechanisms used into by
theautophagy
mechanisms used by
to regulate autophagy
PD-L1 to regulate
expression. PD-L1 suggest
These reviews expression.
and
These
emphasize the bidirectional regulation that exists among these biological processesthese
reviews suggest and emphasize the bidirectional regulation that exists among and,
biological
based on this,processes
proposeand, based
new on this,strategies
treatment propose new treatment
[34,38,39]. strategies
However, [34,38,39].
a better How-
understand-
ever,
ing isarequired
better understanding
concerning theisnon-immune
required concerning
intrinsicthe non-immune
functions of PD-L1intrinsic functions
and their of
potential
PD-L1
influence andon their potentialininfluence
autophagy the contexton autophagy in thethe
of cancer. With context of cancer.
motivation With the moti-
of combatting the
vation
struggles of combatting
imposed by the struggles
cancer, thisimposed
review isbydevoted
cancer, this review is and
to exploring devoted to exploring
delineating new
and delineating new discoveries on the intrinsic immune-independent
discoveries on the intrinsic immune-independent functions of PD-L1 and its impact functions of PD-L1 on
and its impact
autophagy, andon howautophagy, and howthe
this can influence this can influence
efficacy of current thetherapies
efficacy or of allow
currentustherapies
to define
or
newallow us to define
strategies to fightnew strategies
against to fight against this disease.
this disease.

Figure 1. Schematic representation of PD-L1. PD-L1 is a transmembrane glycoprotein comprising

Figure 1. Schematic representation of PD-L1. PD-L1 is a transmembrane glycoprotein comprising
290 amino
290 amino acids,
acids,grouped
groupedinto
intotwo
twodomains
domains(IgV
(IgV
andand IgC),
IgC), followed
followed by by a short
a short flexible
flexible stem.
stem. It
It has
has a hydrophobic transmembrane (TM) domain, as well as a small intracellular
a hydrophobic transmembrane (TM) domain, as well as a small intracellular (IC) domain of 30(IC) domain of
30 amino
amino acids.The
acids. The3D3Dimage
image shown
shown is from
fromthetheProtein Data
Protein Bank
Data and and
Bank is available at https:
is available at
https://www.rcsb.org/structure/3bis
//www.rcsb.org/structure/3bis (accessed
(accessed onSeptember
on 21 21 September 2023).
2023).

2. Overview of the Clinical Significance of PD-L1 in Cancer

Currently, the association of PD-L1 expression in various cancers with a higher risk
of tumor progression is being studied, given its relationship with cancer immune escape.
The PD-1–PD-L1 axis is considered to be an important control point in the treatment of
Int. J. Mol. Sci. 2023, 24, 15016 4 of 19

these patients [40–42]; therefore, PD-L1 expression is one of the most important factors
affecting the effectiveness of PD-1/PD-L1 blockade [43]. The main challenge is to determine
whether the expression of PD-L1 and its regulation are associated with a good clinical
response; currently, this question is under constant scrutiny. Numerous studies have
linked PD-L1 overexpression to specific adverse clinicopathological features. Firstly, the
overexpression of PD-L1 is associated with a more aggressive phenotype and a poorer
prognosis in some cancers, such as gastric cancer, hepatocellular carcinoma, renal-cell
carcinoma, esophageal cancer, pancreatic cancer, ovarian cancer, bladder cancer, and breast
cancer [44–51]. This is due to PD-L1 generating an immunosuppressive tumor environment,
avoiding T-cell activation and the subsequent antitumor immune response. Additionally,
the prognostic value of PD-L1 expression in lung cancer [52,53], colorectal cancer [54,55],
and melanoma [56,57] remains controversial. Several factors, such as the tumor type and
stage, low immunogenicity in tumor cells, the recognition of tumor-specific antibodies as
autoantigens, and tumor surface antigen modulation [58,59], could explain this discrepancy.
In other types of cancer, such as thymoma, squamous-cell carcinoma of the lung, and
cervical cancer, PD-L1 expression is not of prognostic value [58]. It is known that the
inhibition of these checkpoints results in the apoptosis of regulatory T cells (Tregs) and
enhances the immune response of effector T cells against tumor-specific antigens [60].
Nevertheless, the clinical achievements observed with PD-1/PD-L1 immune checkpoint
therapy are not as expected, as patient responses to the treatment exhibit a degree of
heterogeneity and unpredictability. The response to immune checkpoint inhibitors targeting
PD-1/PD-L1 is influenced by complex genetic and epigenetic interactions between immune
cells and tumor cells [61]. Additional, patient-specific factors, such as age and the presence
of comorbidities, could influence their response to immunotherapy [40,62]. The predictive
value of PD-L1 in response to PD-1/PD-L1 antibodies across various tumor types is still
uncertain, and the interpretation of PD-L1 expression in tumors continues to be a subject of
debate, requiring a comprehensive understanding.

3. PD-L1 Expression and Its Induction Factors

After the discovery of a molecule called programmed death 1 (PD-1), an important
negative regulator of the immune system and a member of the immunoglobulin superfamily
that contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic
tail [63], an investigation was conducted to identify a B7 homolog (B7-H1), which was
termed PD-1 ligand (PD-L1) [35]. Next, a second ligand for PD-1, characterized as a B7
homolog (PD-L2), was identified [64]. Together with cytotoxic T-lymphocyte-associated
protein 4 (CTLA-4), PD-1 has been found to be the most reliable drug target in the treatment
of advanced cancers. PD-1 is expressed on the surface of immune cells, commonly on
activated T cells, B cells, and NK cells [23]. Upon ligation with PD-L1, PD-1 undergoes
conformational changes that result in the recruitment of the phosphatases SHP1 and
SHP2 and the dephosphorylation of downstream effectors, such as Syk, PI3K, ZAP70,
and CD3ζ [65]. Moreover, the activation of PD-1 affects downstream signaling pathways
such as PTEN-PI3K-Akt and RAS-MEK-ERK signaling [66,67], resulting in the inhibition
of cell proliferation, cytokine production, and cytotoxic activity in effector immune cells,
which promotes the immune escape of tumor cells. The expression of PD-L1 was initially
detected in non-lymphoid organs, such as the heart, placenta, vascular endothelial cells,
astrocytes, corneal epithelial and endothelial cells, and lungs, in both human and mouse
tissues [64]. Afterwards, PD-L1 expression was identified in hematopoietic cells including
T cells, B cells, macrophages, dendritic cells (DCs), and mast cells [68]. Moreover, in the
tumor microenvironment, activated T cells and cancer-associated fibroblasts also express
PD-L1 [59]. In fact, PD-L1 protein expression in tumor cells and in infiltrating immune cells
is a biomarker in cancer immunotherapy. However, PD-L1 expression is not universally
distributed across all cancer cells. Theelen et al. demonstrated the absence of PD-L1 in
tumoral cells in non-small-cell lung cancer (NSCLC); they suggested that impairment of
IFN-γ signaling in tumor cells could be the cause of this phenomenon [69]. The lack of
Int. J. Mol. Sci. 2023, 24, 15016 5 of 19

PD-L1 upregulation by either tumor cells or tumor-infiltrating immune cells has also been
found in biopsies from patients with other types of cancer, such as melanoma, renal-cell
carcinoma, colorectal cancer, gastric cancer, and head-and-neck squamous-cell carcinoma,
which display patterns with little or no tumor-infiltrating immune cell action [43]. On
the other hand, the overexpression of PD-L1 can be modulated via immune mediators,
oncogenic pathways, cellular stress, and epigenetic mechanisms [70]. We will now present a
general overview of the main factors involved in the overexpression of the PD-L1 molecule
in the context of cancer.

3.1. Cytokines
It is known that PD-L1 is not usually expressed in normal cells; however, its overex-
pression is induced in tumoral tissues [71]. This expression can be a result of the conditions
of the tumor microenvironmental in relation to the adaptive immune response against
cancer cells. The recruitment of immune cells in cancer tissues promotes an inflammatory
microenvironment with the release of an array of inflammation mediators, including IFN-γ,
that favor the expression of PD-L1 in cancer cells [72]. Interferon regulatory factor-1 (IRF-1),
a transcription factor, has been associated with the positive regulation of PD-L1 [73]. More-
over, a recent study reported a synergistic effect of IFN-γ and IL-1β on PD-L1 expression in
hepatocellular carcinoma, mediated by the increase in IRF-1 and the IFN-γ receptor expres-
sion induced by IL-1β [74]. In addition, the Janus kinase/signal transducer and activator of
transcription (JAK/STAT1) pathways, as crucial players in promoting the cellular responses
induced by IFN-γ, have been implicated in the increased expression of PD-L1 in colorectal
carcinoma, gastric cancer, and pancreatic cancer [75–77]. Moreover, the overexpression of
PD-L1 in tumor cells can be due to the activation of signal traducers induced via onco-
genic pathways [78], as has been described in melanoma, with oncogenic BRAF(V600E)
signaling inducing IL-1α/β production, with a subsequent upregulation of PD-L1 in the
tumor stroma [79]. As the main signaling pathway involved in the regulation of PD-L1
is the JAK/STAT pathway, it is possible to hypothesize that any stimuli that trigger this
pathway can cause the overexpression of PD-L1. This was proven to be true in extranodal
natural killer/T-cell lymphoma, where the granulocyte–macrophage colony-stimulating
factor (GM-CSF) induced a high expression of PD-L1, mediated by STAT5 mutations and
JAK2 hyperphosphorylation [80]. Other molecules produced by cells engaged in the tumor
microenvironment, such as CXCL5 produced by cancer-associated fibroblasts, are also
responsible for increases in PD-L1 [81]. On the other hand, a recent study carried out
using the tumor tissues of 148 patients with primary breast cancer correlated the high
levels of PD-L1 with low circulating values of vascular endothelial growth factor (VEGF),
tumor necrosis factor-beta (TNF-β), and interleukin 15 (IL-15) [82]. However, the authors
highlighted that more systematic analyses are necessary because, in other types of cells, the
opposite effect has been reported for IL-15. For instance, IL-2 and IL-7, in addition to IL-15,
have induced the expression of PD-L1 in purified T cells in vitro [83].

3.2. Chemotherapy
In addition to cytokines in the tumor microenvironment inducing an increase in the
expression of PD-L1, other factors have been associated with this effect. In attempts to
investigate the potential effectiveness of combined chemotherapy together with anti-PD-L1
immunotherapy, some data have shown that chemotherapy has an inductor effect on PD-L1
expression. In urothelial carcinoma, the administration of neoadjuvant chemotherapy
increased PD-L1 expression levels [84]. Additionally, paclitaxel treatment induced the
expression of PD-L1 through the MAPK pathway in models of the human colorectal ade-
nocarcinoma cell line SW480 and the hepatocellular carcinoma cell line HepG2 [85]. In
breast cancer cells, the chemotherapeutic agent doxorubicin had a dual effect on PD-L1
expression: it was effective in downregulating the cell surface expression of PD-L1, but it
also showed an upregulation of this molecule in the nucleus. This effect was associated
with the involvement of the PI3K/Akt pathway [86]. Along the same line of thinking,
Int. J. Mol. Sci. 2023, 24, 15016 6 of 19

a study on esophageal squamous-cell carcinoma reported the induction of PD-L1 after

chemotherapeutic (carboplatin plus paclitaxel and 5-FU with cisplatin) treatments, medi-
ated by the MAPK/ERK pathway [87]. 5-Fluorouracil (5-FU) also caused the induction of
PD-L1 in gastrointestinal cancer cell lines [88]. Moreover, an increase in PD-L1 expression
levels was demonstrated in H22 hepatoma cells treated with cisplatin. This induction was
also mediated by the MAPK/ERK pathway [89].

3.3. Effect of the Activation of Toll-Like Receptors (TLRs) on PD-L1 Expression

Other interesting factors involved in increases in PD-L1 are still being discovered. For
instance, an association between TLR activation and the PD-L1 molecule is currently being
researched. Considering that, in some cancers, infections can be related to tumor regression,
the impact of TLR activation on PD-L1 expression has been investigated. In neuroblastoma,
TLR3 triggering has induced the upregulation of both PD-L1 and MHC class I [90]. This
result is consistent with the findings in glioblastoma, in which PD-L1 upregulation is also
mediated via TLR3 triggering [91]. In this context, the signaling of TLR7/8, in addition to
an increase in ROS mediated by the human oncovirus EBV, initiated PD-L1 upregulation
through STAT3 activation [92]. In normal CD90(+) myofibroblasts/fibroblasts (CMFs), an
upregulation of PD-L1 was reported after TLR4 activation, with involvement from the
MyD88/JAK2/NF-κB pathways [93]; this finding is consistent with the interplay between
high PD-L1 expression and TLR4 expression levels that has been reported in colorectal
cancer [94]. However, more studies are needed in order to establish the interconnection of
TLR signaling and other pattern recognition receptors (PRRs) with the signaling pathways
that promote PD-L1 overexpression.

3.4. Hypoxia
The tumor microenvironmental is highly complex, and hypoxia and metabolic fac-
tors are environmental cues to which the cells recruited in the tumor are exposed. Some
in vitro studies, using models of human breast cancer cells, human prostatic carcinoma
cells, mouse B16-F10 melanoma, and mouse tumor models, have revealed a relationship
between hypoxia and an increase in PD-L1 levels that is dependent on the transcription
factor hypoxia-inducible factor-1α (HIF-1α) [95]. This effect has also been seen in tumor-
infiltrating myeloid cells, which showed an increase in PD-L1 expression under hypoxic
conditions, with involvement from HIF-1α [96]. As hypoxia is the main microenvironment
factor exhibited in some cancers, such as gliomas, the relationship between PD-L1 and
HIF-1α has been investigated in patients. The findings provided by Ding and colleagues
demonstrated that hypoxia upregulates the PD-L1 molecule by increasing HIF-1α activa-
tion [97]. These studies highlight the role of HIF-1α as a crucial player in the interplay
between hypoxia and PD-L1. Accordingly, the recruitment of HIF-1α by circular RNA
(circPRDM4) also increases the tumoral PD-L1 expression level in hepatocellular carci-
noma [98]. Moreover, the hypoxic microenvironment has resulted in an increase in PD-L1
associated with the self-renewal of endometrial cancer stem-like cells [99]. Remarkably, in
human melanoma cell lines, the expression of PD-L1 was differentially affected by hypoxia,
and the role of HIF-1α was less important compared to the IFN-γ/JAK/STAT pathway
stimulated by IFN-γ [100]. Interesting in vitro data, inconsistent with previous reports,
indicate that, in bladder cancer, hypoxic conditions decrease the expression of PD-L1 at
the RNA and protein levels, and that hypoxia abolishes the IFN-γ-induced increase in
PD-L1. As this report outlined discrepancies in previous studies, the authors suggested
that the upregulation of PD-L1 induced by hypoxia could be tissue-specific. Intriguingly,
this effect was reverted when cells were highly confluent. The authors hypothesized that
a high cellular density caused a decrease in cellular metabolism, with an impact on PD-
L1 expression [101]. Previous studies reporting a decrease in the expression of surface
molecules, such as TGF-beta receptors and TNF receptors, in response to an increased
cell density in fibroblasts and epithelial and myeloid cell lines, could confirm the role of
cellular confluency in PD-L1 expression [102,103]. Although more studies are necessary to
Int. J. Mol. Sci. 2023, 24, 15016 7 of 19

confirm this finding, cellular density, in addition to hypoxia, could become a crucial factor
in controlling the expression of PD-L1.

3.5. Role of Mammalian Target of Rapamycin (mTOR) in the Upregulation of PD-L1

As described above, in the tumor microenvironment, many cues promote the over-
expression of PD-L1 through different signaling pathways. The mammalian target of
rapamycin (mTOR) kinase is a highly conserved regulator of survival signals, and its
activation in the progression of cancer has been implicated in the control of PD-L1 expres-
sion [104]. It is a serine/threonine protein kinase belonging to the phosphatidylinositol
kinase-related kinase (PIKK) family [105]. mTOR is the main central governor of prolifera-
tion and cell growth and survival in mammalian cells [106]. Its role in biological processes
is dependent on a collection of environmental cues, such as oxygen, stress, amino acids, and
growth factors, which promote the activation of the downstream/upstream effectors asso-
ciated with this molecule. The mTOR protein molecule is a core component of two protein
complexes called mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2), which
elicit various downstream signaling processes to regulate cellular functions. mTORC1 is a
complex composed of mTOR, RAPTOR, MLST8 (or GPL), PRAS40, Tti1/Tel2, and DEPTOR.
On the other hand, MLST8, Tti1/Tel2, and DEPTOR, together with RICTOR, mSin1, and
PROCTOR1/2, make up mTORC2 [107]. Both complexes respond to growth factors and
participate in cell metabolism and survival; however, mTORC2 has been less extensively
studied, and its mechanism of activation is not fully known. The upstream effector is PI3K,
and Akt/protein kinase B (PKB) is the main downstream effector [108,109].
The stimulation of mTORC1 is dependent on the activation of the PI3K–Akt signaling
pathway induced by nutrients and growth factors. Additionally, mTORC1 plays a crucial
role in ribosomal synthesis, as well as the synthesis of proteins, lipids, and nucleotides.
Due to the proliferation and survival functions of mTOR, it has been highly implicated
in tumorigenesis [110]. In recent years, controversial evidence that highlights the role of
mTOR and its downstream effectors in the regulation of PD-L1 has emerged.
The following studies have reported an upregulation of PD-L1 via the activation of
mTOR in several cancer cell models: In a gastric cancer organoid model, the expression
of PD-L1 induced by the hedgehog transcriptional effector GLI was mediated via the
activation of the mTOR pathway [111]. In non-small-cell lung cancer (NSCLC), an increase
in PD-L1 was significantly associated with the oncogenic activation of the Akt-mTOR
pathway [112]. In addition, the overexpression of PD-L1 in breast cancer stem cells was
dependent on the activation of mTOR by its upstream effector Notch3 [113]. Moreover,
the upregulation of PD-L1 via metastasis associated with colon cancer protein 1 (MACC1)
implicated the activation of the Akt/mTOR pathway in gastric cancer cells [114]. The
direct interplay between PD-L1 and the activation of mTOR was also found in NSCLC cell
models. Zhang and colleagues demonstrated that the pharmacological inhibition of mTOR
via MTI-31/AZD8055 or rapamycin provoked a reduction in cell-surface PD-L1. With the
use of specific pharmacological inhibitors, the authors established that the reduction in
PD-L1 was due to proteasomal degradation induced mainly by the diminished activity
of mTORC2-Akt [115]. In the same way, a close correlation between cell-intrinsic PD-L1
signals and the activation of mTOR in bladder cancer cells, promoting cell growth and
metastatic cancer spread, has been demonstrated [116].
On the other hand, some findings have revealed that the upregulation of PD-L1 is
closely related to the inhibition of mTOR. The inhibition of this molecule by rapamycin
and Torin 1 caused an upregulation of PD-L1 in NSCLC cell lines [117]. Additionally, in a
renal-cell carcinoma model, the upregulation of PD-L1 was mediated by the translocation
of transcription factor EB (TFEB) induced by the inhibition of mTOR [118]. Studies using
the same cancer model highlighted that the inhibition of mTOR by RADOO1, an analog
of rapamycin, induced an overexpression of PD-L1 [119]. The expression of PD-L1 being
dependent on the inhibition of mTOR has also been reported in non-tumor cells. Wang and
colleagues showed that the inhibition of mTOR by rapamycin in endothelial cells, used as
 closely related to the inhibition of mTOR. The inhibition of this molecule by rapamycin
and Torin 1 caused an upregulation of PD-L1 in NSCLC cell lines [117]. Additionally, in a
renal-cell carcinoma model, the upregulation of PD-L1 was mediated by the translocation
of transcription factor EB (TFEB) induced by the inhibition of mTOR [118]. Studies using
the same cancer model highlighted that the inhibition of mTOR by RADOO1, an analog
Int. J. Mol. Sci. 2023, 24, 15016 of rapamycin, induced an overexpression of PD-L1 [119]. The expression of PD-L18being of 19
dependent on the inhibition of mTOR has also been reported in non-tumor cells. Wang
and colleagues showed that the inhibition of mTOR by rapamycin in endothelial cells,
anused as an alloimmunogenicity
alloimmunogenicity model, increased
model, increased the expression
the expression of PD-L1 ofandPD-L1
PD-L2 and PD-L2 mol-
molecules on
ecules
the on the cell
cell surface. Thissurface. This effect
effect reduced thereduced the proliferation
proliferation and cytokineand cytokine
secretion secretion of
of co-cultured
co-cultured
allogeneic allogeneic
memory CD4+ memory
T cells CD4+
[120]. T
Incells [120]. In
summary, thesummary, the upregulation
upregulation of PD-L1 mediatedof PD-
L1the
via mediated viaorthe
activation activation
inhibition or inhibition
of mTOR signalingof mTOR signaling
is not fully is not and
understood, fullynew
understood,
research
isand new research
necessary in orderis to
necessary
clarify it.in order to clarify it.
Thecumulative
The cumulativeevidence
evidencehighlights
highlights the
thepresence
presenceof ofmultiple
multiplestimuli
stimuliin inthe
thetumor
tumor
microenvironmentthat,
microenvironment that,subsequently,
subsequently, could
could trigger
trigger an increase
an increase in PD-L1
in PD-L1 oncancer
on the the cancer
cell
surface (Figure
cell surface 2). The
(Figure 2).biological consequences
The biological of PD-L1
consequences overexpression
of PD-L1 are under
overexpression are study
under
because, recently,recently,
study because, non-immune functions
non-immune have been
functions haverecognized in this molecule.
been recognized in this molecule.

Figure 2. The main mechanisms that modulate PD-L1 expression in cancer cells: In the tumor mi-
Figure 2. The main mechanisms that modulate PD-L1 expression in cancer cells: In the tumor microen-
croenvironment, several signals can induce PD-L1 overexpression through the activation of down-
vironment, several signals can induce PD-L1 overexpression through the activation of downstream
stream effectors. (1) Hypoxia-inducible factor 1α (HIF-1α), which can also be induced by other stim-
effectors.
uli, such (1)
as Hypoxia-inducible
growth factors, hasfactor 1α (HIF-1α),
been associated which
with the can also be induced
expression of PD-L1.by(2) other
Somestimuli, such
chemother-
asapeutic
growthagents,
factors, hasas
such been associated
paclitaxel with thethrough
or cisplatin, expressionthe of PD-L1. (2) Some
phosphorylation of chemotherapeutic
ERK ½, induce the
1
agents, such of
expression as PD-L1;
paclitaxel or cisplatin,
however, through the
the complete phosphorylation
mechanisms behindof ERK
this 2 , induce
event remainthe expression
unknown. (3)
ofThe
PD-L1; however,
activation the complete
of mTOR throughmechanisms behind
various signals, this
such as event
growthremain unknown.
factors, (3) The activation
triggers signaling cascades
ofthat induce
mTOR the expression
through of PD-L1,
various signals, such aswhich is decreased
growth when signaling
factors, triggers the mTOR inhibitor
cascades rapamycin
that induce theis
used. (4) Cytokines, such as IFN-γ, induce PD-L1 expression through the JAK/STAT
expression of PD-L1, which is decreased when the mTOR inhibitor rapamycin is used. (4) Cytokines, pathway. (5)
The stimulation of some TLRs induces the activation of canonical pathways to
such as IFN-γ, induce PD-L1 expression through the JAK/STAT pathway. (5) The stimulation of regulate PD-L1 over-
expression. Green arrows mean activation vias, red block lines mean inhibition pathways, dotted
some TLRs induces the activation of canonical pathways to regulate PD-L1 overexpression. Green
arrows mean nuclear translocation, black arrow means decreasing.
arrows mean activation vias, red block lines mean inhibition pathways, dotted arrows mean nuclear
translocation, black arrow means decreasing.

4. PD-L1 and Its Non-Immune Functions

The overexpression of PD-L1 in cancer cells has been largely related to the induction
of the anergy and/or apoptosis of PD-1-positive T cells, through which the antitumor
immunological response is subverted. However, current studies have highlighted new
immune-independent functions in PD-L1 based on the signals triggered by its intracy-
toplasmic region. The first work related to the intrinsic immune-independent signals in
PD-L1 was conducted by Azuma et al. [121]. They demonstrated that PD-L1 is implicated
in cancer cells’ resistance against pro-apoptotic stimuli [121]. Moreover, the knockdown
of PD-L1 expression in human gastric cancer cells significantly inhibited tumor growth
Int. J. Mol. Sci. 2023, 24, 15016 9 of 19

and improved the cytotoxic sensitivity to CIK (cytokine-induced killer cell) therapy [122],
suggesting a pivotal immune-independent role of PD-L1. Later, three well-conserved
sequence motifs (“RMLDVEKC”, “DTSSK”, and “QFEET”) were identified in the intracy-
toplasmic region of PD-L1 associated with its non-immune functions. The RMLDVEKC
and DTSSK sequences were involved in cancer cells’ resistance to apoptotic effects induced
by interferons [37]. The regulation of the biological behavior of cancer cells by PD-L1 also
covers the induction of the epithelial–mesenchymal transition, which has been reported
in lung adenocarcinoma, breast cancer cells, and thyroid cancer, among others [123–125].
Moreover, resistance to radiotherapy and chemotherapy has been associated with PD-L1
expression in non-small-cell lung cancer through the regulation of the DNA damage re-
sponse [126,127] and, importantly, the direct regulation of tumor cell metabolism by PD-L1
has been described in sarcoma tumors [128]. Although it is clear that PD-L1 has the function
of governing the intracellular signals involved in the survival and proliferation of cancer
cells independent of T cells, the mechanism for this has not, to date, been well defined.
Currently, there is little information regarding the downstream signaling effectors of
PD-L1, and it is unknown how this molecule activates or deactivates signals that culminate
in the survival of cancer cells. The increased detection of Akt-1 in co-immunoprecipitation
with PD-L1 in HNSCC cell lines, along with the recent description of the intracellular
signalosome of PD-L1, highlight how it functions immune-independently, regulated by the
mTOR-Akt pathway [37,129], which could explain the impact of the intrinsic functions of
PD-L1 on the cellular processes that culminate in the sustained proliferation and growth of
cancer cells.
The intrinsic effect of PD-L1 on tumor growth has been described in various cancer
types. In melanoma and in ovarian cancer cells, PD-L1 stimulates tumor cell proliferation
and alters autophagy through the regulation of mTOR [130], in addition to promoting the
generation of tumor-initiating cells driven by mTORC1 [131]. In leukemia, the downregu-
lated PD-L1 expression inhibits cell proliferation with the induction of G2/M-phase arrest
and apoptosis through the PI3K-Akt signaling pathway [132]. The involvement of the
Akt-mTOR pathway as a downstream effector triggered by PD-L1 has also been reported in
processes related to invasion and metastasis, such as the epithelial–mesenchymal transition
(EMT) process in hypopharyngeal squamous-cell carcinoma (HSCC) [133], as well as in
chemotherapy resistance in bladder cancers [116].
In addition to the modulation of signals triggered via mTOR activation, new discover-
ies have been described. Experiments conducted on cancer cell lines have demonstrated
that the conserved RMLDVEKC motif of the PD-L1 intracytoplasmic tail is related to the
inhibition of STAT3 Y705 phosphorylation and the prevention of STAT3 upregulation in
the line to avoid IFN cytotoxicity [134]. The investigation of signal transduction events
induced by PD-L1 is ongoing, and further studies are needed in order to discover the
target cytoplasmic effectors triggered by the activation of the PD-L1 molecule, as well as
how those effectors are interconnected to modulate the biological events implicated in
cancer progression.

5. Autophagy Is Controlled by Intrinsic Signaling of PD-L1

Remarkably, an association between autophagy and PD-L1 expression has recently
emerged. Despite there being few reports on this topic, a bidirectional effect along the
autophagy–PD-L1 axis seems possible. However, the approach that explores the role of
autophagy as a regulatory pathway of PD-L1 expression is the most known. Indeed, a
study found that pharmacological inhibition of autophagy increases the expression of
PD-L1 in gastric cancer through the p62/SQSTM1-NF-κB pathway [32]. In line with this
result, a recent work reported that andrographolide, a principal active component in
Andrographis paniculate, caused the selective autophagic degradation of PD-L1, mediated by
the inhibition of STAT3 phosphorylation and the accumulation of p62 [135]. In addition,
verteporfin suppressed the intrinsically expressed PD-L1 and the interferon-induced PD-L1
expression though autophagy [33]. Moreover, the autophagy induced by apatinib decreased
 study found that pharmacological inhibition of autophagy increases the expression of PD-
L1 in gastric cancer through the p62/SQSTM1-NF-κB pathway [32]. In line with this result,
a recent work reported that andrographolide, a principal active component in Androgra-
phis paniculate, caused the selective autophagic degradation of PD-L1, mediated by the
Int. J. Mol. Sci. 2023, 24, 15016 inhibition of STAT3 phosphorylation and the accumulation of p62 [135]. In addition, 10 ofver-
19
teporfin suppressed the intrinsically expressed PD-L1 and the interferon-induced PD-L1
expression though autophagy [33]. Moreover, the autophagy induced by apatinib de-
creased PD-L1 expression
PD-L1 expression in lungcells
in lung cancer cancer cells through
through the ROS/Nrf2/p62
the ROS/Nrf2/p62 pathwaypathway
[136]. [136].
The
The PD-L1 molecule and its relationship with ATG proteins have
PD-L1 molecule and its relationship with ATG proteins have also started to be exploredalso started to be ex-in
plored in
relation to relation
tumor cell to tumor cellInteresting
invasion. invasion. Interesting
data indicatedatathat
indicate that the overexpression
the overexpression of ATG7
of ATG7PD-L1
elevates elevates PD-L1
protein protein expression
expression through thethrough the downregulation
downregulation of forkheadofbox forkhead
(FOX)O3a box
(FOX)O3a
protein proteinand
expression expression
a decreaseand in amiR-145
decrease in miR-145
promoter promoter[137].
transcription transcription
Moreover,[137]. the
Moreover,
invasion and the invasion and
metastasis metastasis
associated withassociated
tumor-derivedwith tumor-derived smallvesicle
small extracellular extracellular
(sEV)
vesiclecould
PD-L1 (sEV)bePD-L1
avoided could be avoided
because autophagybecause autophagy
activation activation via
via temsirolimus temsirolimus
(TEM), an FDA-
approved anticancer drug, suppressed the cellular PD-L1 levels and PD-L1 levels in and
(TEM), an FDA-approved anticancer drug, suppressed the cellular PD-L1 levels sEVsPD- in
L1 levels in sEVs in a dose-dependent manner in cellular models of breast
a dose-dependent manner in cellular models of breast cancer [138]. Together, these studies cancer [138].
Together,
strongly these that
suggest studies
the strongly
activationsuggest that theregulates
of autophagy activation of autophagy
PD-L1 expression regulates PD-L1
(Figure 3A,B).
Itexpression
is known that (Figure 3A,B).
a high It is known
expression that is
of PD-L1 a related
high expression of PD-L1 and
to poor prognoses is related to poor
low survival
prognoses
rates and low
in patients. survival
Therefore, rates in
several patients.
ongoing Therefore,
studies proposeseveral ongoing studies
the modulation propose
of autophagy,
inthe modulationwith
combination of autophagy,
immunotherapy, in combination with immunotherapy,
as an alternative as an
strategy for treating alternative
cancer in its
strategy for
advanced stages. treating cancer in its advanced stages.

Figure3.3. A
Figure A schematic
schematicrepresentation
representationofofthe bidirectional
the autophagy/PD-L1
bidirectional autophagy/PD-L1 relationship: The right
relationship: The
side shows the main findings related to the effects of the activation (A) or inhibition (B) of autophagy
right side shows the main findings related to the effects of the activation (A) or inhibition (B) of
on PD-L1 expression. The left side represents the effects of the intrinsic non-immune functions of
autophagy on PD-L1 expression. The left side represents the effects of the intrinsic non-immune
PD-L1 and the known downstream molecules that culminate in the disruption (C) or activation (D)
functions of PD-L1
of autophagy. andarrows
Green the known
meandownstream molecules
activation vias, thatlines
red block culminate in the disruption
mean inhibition (C) red
pathways, or
activation
dotted line(D) of autophagy.
means Green
hypothetical arrowsblack
pathway, meanarrows
activation vias,upred
aiming block
mean lines mean
increasing, inhibition
black arrows
pathways,
aiming downred mean
dotteddecreasing.
line means hypothetical pathway, black arrows aiming up mean increasing,
black arrows aiming down mean decreasing.

The other approach to the autophagy–PD-L1 interplay is to explore the effect of the
intracellular signaling of PD-L1 on autophagy. The activation or inhibition of autophagy
is a process closely related to both the mTORC1 and mTORC2 complexes. mTORC2
indirectly inhibits autophagy through the Akt1–FOXO3a axis, while mTORC1 inhibits
autophagy through the direct hyperphosphorylation of ULK1 and ATG13 under nutrient-
rich conditions [139]. As recent reports have demonstrated that mTOR is a potential
target for the signaling of the intracytoplasmic tail of PD-L1, it has been suggested that
autophagy could be indirectly controlled by the non-immune functions of PD-L1. It is
well known that autophagy is negatively regulated by mTOR activation. This fact is
consistent with the findings in mouse melanoma and in both mouse and human ovarian
Int. J. Mol. Sci. 2023, 24, 15016 11 of 19

cancer cells, in which a high expression of PD-L1 was correlated with high mTORC1
activity and reduced basal autophagy [130,140]. However, the intrinsic effect of PD-L1 on
autophagy seems to depend on the type of cell. In bladder cells, autophagy is promoted
by intrinsic PD-L1 signals consistent with the dampened mTORC1 response and changes
in the LC3-II/LC3-I ratio. The use of chloroquine and 3-methyladenine as pharmacologic
autophagy inhibitors confirmed that both steady-state autophagy and autophagic flux
are promoted by bladder-cell-intrinsic PD-L1 [116], contrary to the results described in
melanoma and ovarian cancer cells, where starvation-induced autophagy was inhibited
by an increase in mTORC1 and mTORC2 signals [130]. Furthermore, the increase in PD-
L1 overexpression via neoadjuvant chemotherapy (NACT) in gastric cancer induced a
decrease in the Akt/mTOR signaling cascade, which was associated with the initiation of
autophagy [141]. It is known that autophagy is a complex process, involving a series of
molecules that activate in cascade; unfortunately, a direct relationship between intrinsic
PD-L1 signaling and a specific autophagy protein remains unknown in a lot of cancers, but
in some cancers this research is in progress.
The dissection of target molecules downstream of PD-L1 signaling has been advanced
in PD-L1-overexpressed U251 glioma cells, in which expression was positively correlated
with the PI3K/Akt pathway, p62/SQSTM1, and β-actin. To elucidate the molecular mecha-
nism of PD-L10 s action, a PD-L1 series truncated via deletion was used. The results showed
that a PD-L1 128-237 fragment was required for preferential binding of Akt1 and Akt2.
The PD-L1–Akt interaction led to a modification in the cellular morphology depending
on the F-actin cytoskeleton and, importantly, it showed lower Beclin-1 and LC3 levels,
consistent with the suppression of autophagy and an increase in p62 [142]. These studies
are controversial, and further experimentation is required in order to attain a general view
of the role of PD-L1 in autophagy. These contradictory results could be due to the type of
cancer, the stage of the cancer, or the downstream molecules activated after PD-L1 signaling.
Furthermore, it is necessary to establish and clarify the interconnection between PD-L1 and
both mTOR complexes, as well as how these molecules influence autophagy.
The control of autophagy via the intrinsic effect of PD-L1 is dependent on the activa-
tion of positive or negative regulatory molecules. A relevant study using hepatocellular
carcinoma models correlated tumor growth with the induction of autophagy. Later immune
precipitation assays showed an interaction of PD-L1 with ATG13 (an accessory protein
of the ULK1 kinase complex, an initiator of autophagy), which caused an increase in au-
tophagy [143]. These results indicate that the intrinsic signaling of PD-L1 can culminate in
the activation of key molecules for triggering autophagy (Figure 3C,D), thus allowing cells
to tolerate unfavorable conditions and continue to grow and escape the immune response.
Together, these studies highlight the bidirectional interplay between PD-L1 and au-
tophagy (Figure 3). Currently, few molecular players and signaling pathways have been
recognized from both angles. Mechanistically, the activation or inhibition of autophagy can,
in turn, regulate the expression of PD-L1 through the involvement of STAT3, NF-κB, or p62.
On the other hand, the intrinsic functions of PD-L10 s downstream signaling can disrupt or
activate autophagy, with the participation of mTOR, Akt, p62, or ATG13.
To date, the research on the signaling of PD-L1 that culminates in the activation or
deactivation of autophagy is in its infancy. The few studies are controversial, and further
research is necessary in order to obtain a clear view of the effect of PD-L1 signaling on
autophagy, as well as the molecules involved. In advanced stages of cancer, the negative
regulation of autophagy via high levels of PD-L1 could be an advantageous intervention
for disrupting cancer cells’ sources of nutrients and energy, as well as their adaptability to
stress. However, the clinical efficiency should be evaluated considering the participation of
mTOR and other crucial players whose perpetual activation could control cell growth and
cancer cell metabolism. Furthermore, the inhibition of autophagy also blocks the normal
catabolic degradation of PD-L1 and could inhibit the functionality of immune cells. Due to
the complex dual role of the autophagy–PD-L1 axis, potential clinical interventions must
tread a delicate balance regarding the activation or inhibition of the processes involved, as
Int. J. Mol. Sci. 2023, 24, 15016 12 of 19

well as the stage of the tumor and the types of cells affected by the treatments, in order to
be successful.

6. Conclusions
There have been scientific and valid considerations related to the relevance of inducing
the upregulation of PD-L1 in tumor cells, mainly because a better recognition by the
therapeutic anti-PD-L1 could be achieved. However, the new research that highlights
the role of the non-immune intrinsic functions of PD-L1 in the growth and survival of
cancer cells forces us to reconsider this hypothesis. Moreover, the low response rates
(less than 40%) of patients to PD-1/PD-L1 blockade therapy illustrate the need for a
better understanding of the functions of PD-L1 and the biological impact of its negative
or positive regulation in the tumor environment. The presence of numerous cues in the
tumor microenvironment that induce the overexpression of PD-L1 highlights the potential
increase in intracellular signals triggered by this molecule. What biological phenomena
are initiated after the signaling of PD-L1? Some of them, such as apoptosis, chemotherapy
resistance, and tumoral metabolism, are being studied, with controversial results in some
cases. The latest research on this topic has indicated that autophagy is another potential
target process for PD-L1 signaling. Although much remains to be elucidated, PD-L1 seems
to activate more than one signaling pathway and, therefore, can turn autophagy on or
off. In some types of cancer, such as glioblastoma, renal-cell carcinoma, lung cancer, colon
adenocarcinoma, and hepatocellular carcinoma, among others, PD-L1 has been associated
with a poor prognosis. On the other hand, increased autophagy often supports tumor cells’
survival and growth. Thus, the redundancy of these processes could be a vicious circle
that must be pharmacologically broken. In fact, there are ongoing clinical trials for NSCLC,
breast cancer, metastatic pancreatic adenocarcinoma, advanced melanoma, pancreatic
cancer, and metastatic renal-cell carcinoma with a combination of PD-L1 and autophagy
inhibitors. However, the relevance of pharmacologically modulating the expression of
PD-L1 should be evaluated, with a complete view of its implications for autophagy. This
review emphasizes our current understanding related to the regulation of autophagy via
the intrinsic functions of overexpressed PD-L1, but whether or not the downregulation of
PD-L1 controls autophagy remains unknown. In addition, further experiments are needed
in order to elucidate the molecules involved in the downstream signaling of PD-L1 that
could culminate in the activation or deactivation of the autophagy machinery. Meanwhile,
these findings can help in the design of new combined therapy strategies to improve the
efficacy of cancer treatments.

7. Methodology
This review was written using information sourced from PubMed. The keywords
searched were “autophagy AND PD-L1”, “autophagy AND cancer”, “PD-L1 AND mTOR”,
and “PD-L1 AND hypoxia”. The information was filtered to select works published in the
last 10 years, except for some references related to general information about autophagy,
PD-L1, mTOR, and cancer.

Author Contributions: B.E.G.-P. was responsible for the conceptualization, investigation, and
writing—original draft preparation. C.P.-T. summarized the information on immunology and pre-
pared the figures. S.L.B.-U. participated in the research related to the autophagy–PD-L1 relationship.
J.C.-C. revised the literature associated with the PD-L1 molecule. N.S.C.-J. summarized the literature
concerning autophagy in cancer. All authors participated in the final editing of the manuscript. All
authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by the Secretaría de Investigación y Posgrado del Instituto
Politécnico Nacional (SIP-IPN 20220559 and 20230384).
Institutional Review Board Statement: Not applicable.
Data Availability Statement: The data presented in this study are available in PubMed.
Int. J. Mol. Sci. 2023, 24, 15016 13 of 19

Acknowledgments: B.E.G.-P. kindly acknowledge to the Instituto Politécnico Nacional, CONAHCYT,

COFAA-IPN, EDI-IPN and SNI for their fellowships and financial support. S.L.B.-U. received
fellowship from EDI-IPN and SNI. J.C.-C and N.S.C.-J. received scholarships from SNI. C.P.-T received
scholarship from CONAHCYT.
Conflicts of Interest: The authors declare no conflict of interest.

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