





































Berkeley
Pharma Tech
Journal of Medicine

Correspondence: 
sanchithabpt1@gmail.com

Keywords:
Tumor microenvironment 
Immunotherapy
Cytotoxic t lymphocytes
PD-1
CTLA-4
Lactic acid
Non-small cell lung cancer 
(NSCLC)

Submitted August 11, 2023 
Accepted May 23, 2024 
Published June 28, 2024

Full Open Access 

Creative Commons Attribution 
License 4.0 

Abstract
The tumor microenvironment (TME) surrounds the tumor and includes blood vessels, 
immune cells, fibroblasts, signaling molecules, and the extracellular matrix. This 
review examines the cellular components and pathways within the TME, highlighting 
their potential as targets for immunotherapy. It also covers recent advances from the 
past several years in TME, immunotherapy, and combination therapy. The review 
emphasizes the role of CD8+ T cells in the TME and their relevance to 
immunotherapy. It discusses various T cell-targeted treatments, including PD-1/PD-
L1, CTLA-4, VEGF, Interferon-ɣ, LAG-3, and ER stress-XBP1. Recognizing the
complexity and uniqueness of each tumor's immunotherapy network, the review aims 
to understand and compare the TMEs of different cancers and the respective 
immunotherapies. Cancers covered include non-small cell lung Cancer (NSCLC), 
pancreatic ductal adenocarcinoma (PDAC), cervical cancer, chronic lymphocytic 
leukemia, and gastric cancers. The review also addresses future research directions 
and applications of immunotherapies, aspiring to advance TME understanding and 
research.

Decoding the Interplay: Exploring 
Immunotherapy Resistance in the Tumor 
Microenvironment
By: Sanchitha Kannabran, Akshaya Ajan, Leanne Lui, Zaden Yet



1. Introduction

The tumor microenvironment (TME) constitutes the immediate 
surroundings of a tumor, forming a complex ecosystem inclusive of nearby 
blood vessels, immune cells, �broblasts, signaling molecules, and 
the extracellular matrix (ECM).1 Within the TME, there exist hypoxic 
and acidic conditions, alongside altered expression patterns of ECM 
proteins. These conditions foster the presence of resident and 
in�ltrating immunosuppressive cells, trigger the expression of immune 
checkpoint proteins, and promote the exclusion and exhaustion of 
cytotoxic T lymphocytes (CTLs).2 Such circumstances serve as the 
foundation for immunotherapy targeting the TME. While contemporary 
interest in TME immunotherapy appears recent, investigations into 
utilizing immune cells for combating tumors date back to the 1900s.3 

New studies are directed towards pinpointing cellular pathways within the 
TME with the use of immunotherapy components to hinder growth. 
Among the primary pathways are lactic acid accumulation, metabolic 
processes, and diverse signaling routes within the TME. 5,6,7  All these 
pathways represent potential targets for immunotherapy interventions. 
Moreover, treatments are geared towards enhancing the immune system's 
ability to eradicate cancer cells and impede their proliferation. To achieve 
this goal, two primary strategies are employed: immune 
checkpoint inhibition and adoptive cellular therapy (ACT).4 Immune 
checkpoint inhibition involves obstructing certain proteins, known as 
checkpoints, to enhance the responsiveness of immune cells.4  Adoptive cell 
therapy (ACT) entails administering T cells to patients to bolster their 
ability to combat tumor cells.4  

In this discussion, our focus lies on T cell-based immunotherapies, 
including anti-PD-1/PD-L1, anti-CTLA-4, VEGF, Interferon-ɣ (IFN-ɣ), 
LAG-3, and ER stress-XBP1. However, the complexity of immunotherapy 
arises from the variable responses of individual cancers to di�erent 
immunotherapeutic approaches. This review delves into the distinctive 
attributes of cancers such as non-small cell lung cancer (NSCLC), 

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melanoma, pancreatic cancer, cervical cancer, and chronic lymphocytic 
leukemia.

2. Immune Cell Overview

The extracellular matrix (ECM) is comprised of collagen, �bronectin, 
elastin, and laminin, serving as the structural framework within the tumor 
microenvironment (TME). Within this environment, various immune cells 
including T cells, B cells, Natural Killer cells (NK), macrophages (M1 and 
M2), stromal cells, endothelial cells, and cancer-associated �broblasts 
(CAFs) play pivotal roles in either promoting or suppressing tumor 
growth.8

T cells, equipped with T-cell receptors, target speci�c antigens on tumor 
cells, halting angiogenesis—the formation of new blood vessels—and 
leading to tumor cell destruction. However, T cells can become in�ltrated 
and dysfunctional within the immune system.8,9  B cells contribute to 
antibody production, antigen presentation, and cytokine secretion. 8,9  In the 
context of lymphocytes, both T and B cells, particularly tumor-in�ltrating 
lymphocytes (TILs), are crucial in research. While TILs e�ectively eliminate 
tumor cells, they can be recruited by the TME, compromising immune 
response e�cacy.4  

Regulatory T cells (Tregs) maintain immune response balance, but when 
recruited to the TME, they hinder T cell formation, posing a danger to 
immune function. Consequently, immune mechanisms originally aimed at 
protecting the body now facilitate TME growth.10

NK cells surveil the bloodstream for tumor cells, inhibiting metastasis.8,9  
Macrophages regulate immune responses by phagocytosing pathogens and 
presenting antigens. Notably, increased macrophage in�ltration in tumors, 
particularly the M2 phenotype, and cytokine secretion, support tumor 
growth.8,9

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Figure 1: This figure illustrates the distinct contributions of various immune cells to the 

Tumor Microenvironment (TME). It delineates the overall immune response attributed to 

each mentioned immune cell type: T cells, B cells, Macrophages (M1 and M2), Natural 

Killer cells (NK), Tregs, and CD8+ cells. The upper side represents the positive immune 

response, while the lower side depicts the autoimmune suppressive response.

Stromal cells, including endothelial cells, �broblasts, adipocytes, and 
stellate cells, play crucial roles in tumor development. Tumor cells 
recruit these supporting cells from nearby tissue to aid in tumor 
formation. Stromal cells secrete various factors that in�uence 
processes like angiogenesis, proliferation, invasion, and metastasis.8,9

Endothelial cells, for instance, are pivotal in orchestrating blood 
vessel formation and signi�cantly contribute to cancer progression by 
promoting cancer cell migration, invasion, angiogenesis, and metastasis. 
They transition into cancer-associated �broblasts (CAFs), facilitating 
communication between tumor cells and the tumor 
microenvironment (TME).1 This interaction often leads to the 
disruption of cell connections and detachment. CAFs can derive 
from various immune cells, but within the TME, they become                              

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signi�cant producers of extracellular matrix (ECM), tumor growth 
factors, cytokines, and other essential components. Each stromal cell 
type contributes uniquely to the TME, and targeting their speci�c 
functions presents an opportunity for novel immunotherapeutic 
approaches.1

The immune response involves numerous intricate processes, among which 
angiogenesis stands out—a phenomenon where endothelial cells proliferate 
and migrate, forming new blood vessels.11 This process is pivotal as it grants 
tumors the capability to metastasize, spreading to other locations within the 
body. Conversely, inhibiting angiogenesis can e�ectively curtail tumor 
growth and metastasis.11 For instance, research conducted by Chen et al. 
demonstrates that the administration of anti-malarial drugs like 
dihydroartemisinin and artesunate resulted in a reduction in the size of cell 
lines. These drugs were found to hinder the growth factors crucial for cancer 
cell proliferation, thereby impeding angiogenesis.11

Anti-angiogenic (AA) therapy plays a signi�cant role in remodeling the 
extracellular matrix (ECM), altering the distribution of cell types and 
populations.12 This therapy redistributes pericyte proteins along blood 
vessels, increasing coverage and eliciting a pro-aggressive tumor response. 
Notably, glycosylation of these proteins is speculated to contribute to 
malignant resistance to AA therapy.12 However, a complication arises as 
resistance can develop post-AA treatment, fostering tumor cell migration 
and invasion. Tumor cell receptors possess mechanisms to detect 
AA-induced alterations in their environment, prompting a remodeling of 
the entire tumor microenvironment (TME) to facilitate tumor growth once 
more.12

3. T Cell Based Immunotherapy

This section of the review will delve into several key surface cell receptors 
found on endothelial cells, tumor cells, and T-cells. It will explore their roles 
in promoting tumor growth, strategies to overcome resistance, and the 

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underlying mechanisms of resistance. Emphasis will also be placed on the 
critical functions of in�ltrating tumor lymphocytes and cytotoxic T cells.

Within the tumor microenvironment (TME), various surface cell receptors 
recognize speci�c antigens, initiating signaling cascades that ultimately 
impact downstream events. These cascades often lead to the inactivation or 
impairment of e�ective T-cells, which are typically responsible for targeting 
and eliminating tumor cells. The TME, being highly adaptable, fosters 
conditions conducive to tumor cell growth, proliferation, and survival.13

Several immune response cells contribute to immune resistance, including 
myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), 
tumor-associated macrophages (TAMs), tumor-associated neutrophils 
(TANs), and endothelial cells. The secretion of negative regulatory factors 
by these cells can induce T-cell exhaustion, dysfunction, and apoptosis.13

Figure 2: A. Vascular Endothelial Growth Factor-A (VEGF-A) binds to Vascular 

Endothelial Growth Factor Receptors (VEGFRs) situated on endothelial cell 

surfaces, initiating a series of reactions that stimulate angiogenesis. B. The 

interplay between proteins located on T cell surfaces and their corresponding ligand 

surface cell receptors on tumor cells contributes to T cell exhaustion.

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One e�ective therapeutic approach, immune checkpoint inhibition, has 
demonstrated success in rejuvenating the cytotoxic function of CTLs and 
T-cells. This therapy works by alleviating the suppression of antitumor
immunity, freeing CTLs from exhaustion.13 The FDA has approved
antibodies targeting Programmed Cell Death 1 (PD-1/PD-L1) and
Cytotoxic T Lymphocyte-Associated Protein 4 (CTLA-4) for treating
various cancers. Additionally, ongoing clinical research is targeting other
immune checkpoints like LAG3, CD39, CD73, and CD47, all showing
promising potential in advancing cancer immunotherapy.14

3.1 PD-1/PD-L1

  Immune checkpoint inhibition stands out as an e�ective therapeutic 
approach in reviving the cytotoxic capabilities of CTLs and T-cells. By 
alleviating the exhaustion-induced suppression of antitumor immunity, this 
therapy unleashes CTLs to combat tumors.13 The FDA has approved the 
use of antibodies targeting Programmed cell death 1 (PD-1/PD-L1) and 
cytotoxic T lymphocyte-associated protein 4 (CTLA-4) as treatments across 
various cancer types.13

Numerous other immune checkpoints are currently under investigation in 
clinical research, including LAG3, CD39, CD73, and CD47, all of which 
show promising potential in advancing the landscape of cancer 
immunotherapy.14 Among these, PD-1 is a pivotal protein implicated in T 
cell apoptosis, or programmed cell death. It is predominantly expressed on 
the surface of activated immune cells such as macrophages, dendritic cells, B 
cells, and T cells.14 Notably, PD-1 expression is particularly elevated on 
exhausted T cells, where it plays a role in inhibiting their normal immune 
function. When PD-1 interacts with its ligand receptor, PD-L1, on tumor 
cells, it initiates a series of signaling events that directly impede the response 
of activated cells by enhancing local evasion mechanisms.14,15 These immune 
checkpoint inhibitors (ICIs) interfere with T cell functionality, leading to 

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an increase in exhausted T cell populations, both of which contribute to 
adaptive resistance against immune checkpoint blockade therapy.16

Researchers conducted clinical trials investigating the interaction between 
PD-1 and PD-L1 on cytotoxic T cells in mice. They observed accelerated 
tumor growth, which was mitigated when treated with an anti-PD-L1 
antibody or through PD-1 knockout, resulting in reduced tumor growth. 
Similar �ndings were noted in human trials.17 For instance, Qian et al. 
demonstrated in a study focusing on glioma cancer that tumor-in�ltrating 
T cells become activated and can increase PD-1 expression, leading to T cell 
dysfunction mediated by Immune Checkpoint Inhibitors (ICIs). 
Consequently, the researchers suggested that anti-PD therapy could impede 
glioma cancer progression.17

Another instance illustrating the e�ectiveness of immune checkpoint 
inhibition therapy in microsatellite instability/de�cient mismatch repair 
(MSI/dMMR) tumors comes from the ongoing trial conducted by 
IMHOTEP, which showcases a group of 120 patients bene�ting from 
anti-PD therapy.18 While anti-PD therapy has shown success in certain 
patients, others have exhibited poor responses due to both primary and 
acquired resistance mechanisms working against the treatment. E�ective 
anti-PD therapy hinges on the precise blockade of the PD-1 and PD-L1 
pathways. However, if either protein lacks expression, the treatment proves 
ine�ective against the tumor cells—a direct primary resistance mechanism 
observed in some cases.15 Furthermore, certain cancers lack 
tumor-in�ltrating T cells or PD-L1, rendering them unresponsive to 
anti-PD therapy.15 To combat this adaptive resistance, combination therapy 
involving both immuno- and chemo-therapies has been proposed as a more 
e�ective approach to treating cancer compared to immunotherapy alone.

3.2 CTLA-4

CTLA-4, a protein associated with cytotoxic T lymphocytes, plays a role in 
dampening the anti-tumor immune response by regulating the activation of 
CTLs, thus hindering an e�cient immune reaction.14 Unlike PD-1, which 
manages programmed cell death, CTLA-4 dictates whether a T cell 

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undergoes activation or remains in a state of rest termed exhaustion. It is 
present on the surface of stimulated functional T cells, and activation 
occurs upon stimulation from a T cell receptor.14     

CTLA-4 competes with CD28 for binding to the T cell ligand, blocking the 
crucial costimulation signals required for activation.14 Due to its higher 
a�nity for the ligand, CTLA-4 binds more e�ectively, leading to T cell 
exhaustion and inhibiting activation. Using an antibody that selectively 
targets and binds to CTLA-4 can restore T cell activation by eliminating the 
competition for T cell ligand binding with costimulation signals.14 
Additionally, CTLA-4 is prominently expressed on the surface of Tregs, 
which play a role in immune response suppression.14

Research indicates that CTLA-4 plays a pivotal role in regulating the 
function and production of Tregs,14 which in turn directly suppress the 
activation of target immune cells by increasing CTLA-4 expression.19 
Utilizing CTLA-4 blockade therapy has emerged as an e�ective strategy for 
enhancing anti-tumor immune responses.14 The FDA-approved 
monoclonal anti-CTLA-4 antibody, ipilimumab, has signi�cantly enhanced 
overall survival rates among patients with malignant melanoma.4 It's worth 
noting that while anti-CTLA-4 antibodies show e�cacy in late-stage 
melanoma, their e�ectiveness in other tumor types is limited. Consequently, 
clinical trials are exploring combination therapies to address this limitation.4

3.3 LAG-3

Lymphocyte Activation Gene 3 (LAG-3) serves as an immune checkpoint 
receptor, capable of dampening responses orchestrated by T and NK cells, 
thereby fostering a hyporesponsive condition, which aids tumors in 
escaping immune surveillance. Typically found on activated and exhausted 
T and NK cells, B cells, dendritic cells, and Tregs, LAG-3 signaling inhibits 
T cell proliferation, cytokine generation, and cytolytic activity.20 
Additionally, its presence on Tregs contributes to immunosuppression.20

An illustrative instance of this phenomenon is evident in individuals 
a�icted with chronic lymphocytic leukemia (CLL), where there is 
signi�cant dysregulation of LAG-3. Both NK cells and T cells exhibit 

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heightened LAG-3 expression, and elevated levels of LAG-3 or soluble 
LAG-3 (sLAG-3) are associated with adverse cytogenetics and unfavorable 
outcomes among CLL patients. Consequently, treatment involving the 
application of an anti-LAG-3 blocking antibody called relatlimab to 
peripheral blood mononuclear cells (PBMCs) has demonstrated e�cacy in 
reducing leukemic cell counts and restoring NK cell and T cell mediated 
responses.20 As a result, interventions aimed at reinstating T and NK cell 
mediated responses through LAG-3 blockade have emerged as promising 
therapies for hematological malignancies such as CLL, follicular lymphoma 
(FL), di�use large B cell lymphoma (DLBCL), and acute myeloid leukemia 
(AML).20

3.4 ER Stress/IRE1a-XBP1

A fresh angle in cancer therapy involves focusing on the ER stress pathway, 
with a particular emphasis on the XBP1 gene.21 In a 2022 study conducted 
by Zundell et al., investigating ovarian clear cell carcinomas (OCCC), it was 
discovered that the ARID1A gene, responsible for epigenetically regulating 
gene expression via the SWI/SNF chromatin remodeling complex, is 
mutated in over 50% of OCCCs. This mutation results in inadequate 
expression of ARID1A protein, leading to advanced-stage disease and early 
recurrence.21

This element plays a vital role by transcriptionally inhibiting the 
IRE1𝛂-XBP1 pathway of the ER stress response. Their research using 
mouse models indicates that disabling XBP1 and inhibiting the 
IRE1𝛂/XBP1 pathways signi�cantly enhances the survival rate of mice with 
OCCC, as it suppresses the growth of ARID1A mutant OCCC cells.21 In 
the face of ER stress, the IRE1-𝛂 component, a type of unfolded protein 
response (UPR), undergoes a structural change, splicing the mRNA 
encoding the XBP1 transcription factor. This splicing facilitates the 
translation of XBP1, which in turn aids cancer cell survival by resolving ER 
stress.21

ER stress itself fosters the survival of cancer cells by activating adaptive 
programs through the unfolded protein response (UPR) once detected. 

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Consequently, inhibiting the UPR is emerging as a therapeutic strategy for 
cancers characterized by heightened ER stress response.21 In this study, the 
e�cacy of a therapeutic intervention targeting the IRE1𝛂 RNase, B-I09, 
was examined. By inhibiting IRE1𝛂 RNase activity, B-I09 e�ectively 
suppressed the growth of ARID1A-activated cells in ovarian clear cell 
carcinomas (OCCCs), indicating the potential of targeting the 
IRE1𝛂-XBP1 axis of the ER stress response as a promising approach for 
treating ARID1A mutant OCCCs.21         

A study by Ma et al. illustrated the role of cholesterol, the primary sterol 
distributed throughout the human body, in the ER stress-XBP1 pathway.22 
Through staining techniques to observe cholesterol levels in 
tumor-in�ltrating T cells in mice, researchers found that elevated cholesterol 
content triggers CD8+ T cell exhaustion via the ER stress-XBP1 pathway.22 
Inhibiting the XBP1 pathway or reducing cholesterol levels in CD8+ T cells 
restored normal antitumor function, while increased cholesterol was 
consistently linked to elevated PD-1 expression on tumor-in�ltrating T 
cells.22 Similar patterns were observed in human colon cancer and myeloma 
samples, underscoring the signi�cance of cholesterol content in T cell 
exhaustion.22

3.5 VEGF/VEGF-A:

Vascular endothelial growth factors (VEGFs) are signaling proteins crucially 
involved in the microvasculature of tumors, the suppression of immune 
cells, and the promotion of immunosuppression, both locally and 
systemically, in cancer.19 These proteins are predominantly secreted by the 
endothelial cells lining blood vessels, with additional production occurring 
in immune cells within the tumor microenvironment (TME).19 VEGFs play 
a pivotal role in fostering tumor development and progression by 
interacting with receptors on tumor cells through autocrine and paracrine 
signaling pathways. Among them, VEGF-A primarily binds to VEGFR-2, 
triggering the proliferation and migration of endothelial cells, thereby 
facilitating angiogenesis.19

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VEGF-A boosts the expression of both PD-1 and CTLA-4, dampening the 
body's ability to �ght tumors and reducing the activity of CD8+ T cells by 
transitioning them from an active state to an exhausted one, impairing their 
normal function. Blocking VEGF with anti-angiogenic agents can reverse 
the immune checkpoints' inhibitory e�ects.19 In a phase I trial led by Daniel 
Chiu et al., a combination of anti-PD-1 therapy and antiangiogenic agents 
was used to treat glioblastoma, a challenging form of brain cancer known 
for its resistance to ICI therapy. The �ndings revealed that this combination 
treatment was well tolerated, safe, and did not lead to any previously 
unreported adverse events. Furthermore, the results showed decreased levels 
of VEGF-A and other angiogenic factors in the tumor microenvironment, 
underscoring the relationship between VEGF and PD-1 expression.16

4. Overcoming Resistance to Immune Checkpoint Blockade
Although the immune checkpoint blockade strategy has shown e�cacy in 
reviving the antitumor response within tumor-in�ltrating lymphocytes 
(TILs) and cytotoxic T cells, the tumor microenvironment (TME) employs 
adaptive resistance mechanisms against this therapy. Speci�cally, the 
upregulation of immune checkpoints such as PD-1 and CTLA-4 in 
response to targeted antibodies can foster this adaptive resistance.14 
Moreover, the TME utilizes evasion tactics, such as enhancing PD-1 
expression in response to T cell attacks, leading to the functional 
impairment of TILs.13,17 Additionally, the di�erentiation of CD8+ T cells 
poses a signi�cant challenge, as TILs develop resistance to antitumor 
treatments, resulting in a diverse CD8+ T cell subset.17 Researchers are 
exploring combination therapies, pairing immunotherapy with 
chemotherapy or radiation therapy, to address malignant tumors. In a study 
by Feng Y. et al., a dual gene therapy approach was investigated to counter 
adaptive resistance to immune checkpoint blockade therapy in both CD4+ 
and CD8+ T cells. The scientists developed a dual gene delivery system 
aimed at eliminating tumor adaptive resistance and restoring T cell function 
by modulating the expression of VEGF-A and PD-L1 proteins.14 
Gene-silencing techniques were employed to decrease VEGF-A expression 
in the TME, reducing angiogenic activity and blocking PD-L1 immune 

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checkpoint. The �ndings demonstrated an increase in the number of CD8+ 
T cells expressing granzymes B, leading to inhibited tumor growth.14

Furthermore, increasing VEGF-A gene silencing e�ectively alleviated tumor 
hypoxia. However, it's crucial to regulate the dosage of each treatment, as 
excessive pShVEGF-A antibody treatment can exacerbate tumor hypoxia by 
overly depleting tumor vessels. Upon treating tumor-infected mice with the 
dual gene therapy, scientists observed substantial inhibition of tumor 
growth and prolonged overall survival rates compared to mice treated with 
monotherapy.14 This dual gene therapy not only countered immune 
checkpoint blockade-induced adaptive resistance but also reversed the 
immunosuppressive tumor microenvironment simultaneously. This dual 
gene delivery system represents a promising avenue for immunotherapy 
across various tumor types, though further research is warranted

4.1 Lactic Acid in the Tumor Microenvironment

One of the key areas of exploration for scientists has been the manipulation 
of lactic acid within the tumor microenvironment (TME). Lactic acid, a 
byproduct of altered metabolism, plays a signi�cant role in shaping the 
TME. Its acidic nature fosters various processes including angiogenesis, 
metastasis, and drug resistance. A 2020 study highlighted that heightened 
lactic acid production can detrimentally a�ect anticancer immunity by 
suppressing immune responses due to the low pH environment it creates.7 
Lactic acid impedes the di�erentiation of monocytes into dendritic cells, 
leading to a reduction in antigen-presenting functions. Additionally, it 
hampers the anti-tumoral activities of immune cells like natural killer cells 
and cytotoxic T cells.7 Consequently, the targeting of lactate and lactic acid 
has emerged as a compelling area of focus within contemporary 
immunotherapy research.

Scientists have been investigating the neutralization of lactic acid as a 
potential method. By bu�ering the tumor microenvironment using oral 
bicarbonate and coupling it with anti-PD-1 immunotherapy and adoptive 
T-cell transfer, there's potential for enhancing survival rates.5 Furthermore,
research has shown that V-domain Ig suppressor of T cell activation
(VISTA) can inhibit T cells in an acidic pH environment. Consequently,

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blocking VISTA in conjunction with PD-1 blockade, and the development 
of pH-speci�c antibodies against VISTA, have demonstrated e�cacy in 
tumor rejection.5

Another signi�cant focus lies in targeting the lactate-producing enzyme 
LDH, which shows promising anti-cancer e�ects. However, its impact on 
immune cells remains largely unexplored, as LDH inhibition can decrease T 
cell levels5. An alternative approach involves inhibiting lactate transporters. 
Notably, researchers identi�ed SLC4A4 as the predominant bicarbonate 
transporter in pancreatic ductal adenocarcinoma (PDAC). Inhibiting 
SLC4A4 in PDAC cells reduces TME acidi�cation by accumulating 
bicarbonate in the extracellular space and lowering lactate production. 
Combining SLC4A4 targeting with immune checkpoint blockades has 
been found to overcome immunotherapy resistance.6 Targeting lactic acid 
holds signi�cant promise for advancing immunotherapy in the tumor 
microenvironment, as it plays a pivotal role in TME acidi�cation and 
subsequent immune response suppression.

4.2 Targeting Metabolism in the Tumor Microenvironment

Focusing on metabolism to enhance the tumor microenvironment for 
cancer immunotherapy holds signi�cant promise. Cancer cells exhibit 
heightened metabolic activity, fueling their rapid proliferation. By zeroing 
in on metabolism, scientists can slow down cancer cell spread and impede 
their function. The realm of immune metabolism o�ers potential metabolic 
targets to bolster anti-cancer immunity. The dynamic metabolism of 
immune cells signi�cantly in�uences their functions as well.25

A primary approach involves targeting amino acid metabolism, where 
speci�c amino acids such as glutamine, tryptophan, and arginine have 
emerged as key targets for inhibiting tumor progression and enhancing 
immunity. Glutamine, in particular, plays a vital role as a nutrient for cancer 
cells. Enzymes like glutaminase (GLS) facilitate the conversion of glutamine 
to glutamate, making GLS a prime target to curb cancer cell metabolism 
and glucose utilization. However, targeting GLS poses challenges as cancer 
cells employ alternative methods to boost glucose metabolism. Additionally, 
directing GLS inhibition towards immune cells, particularly T cells, a�ects 

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their di�erentiation, survival, proliferation, and e�ector functions.5 This 
presents a signi�cant hurdle, as it necessitates reducing glutamate levels in 
cancer cells while ensuring adequate glutamine for proper T cell function. 
Consequently, a strategy has been devised to broadly block glutamine 
metabolism alongside anti-PD-1 immunotherapy. This combined approach 
enhances anti-tumor e�ects by dampening tumor metabolism while 
maintaining robust glucose metabolism in T cells.5

Furthermore, researchers have shown keen interest in targeting arginine and 
nitric oxide, delving into amino acid metabolism. Arginine plays a pivotal 
role in cancer and immune cell functions, particularly in proliferation, 
survival, and protein synthesis. The metabolic pathways of arginine heavily 
rely on enzymes like arginase (ARG) and nitric oxide synthase (NOS). 
However, given arginine's signi�cance to both cancer and immune cells, its 
potential as a therapeutic target presents complexities. While arginine 
depletion proves e�ective in certain scenarios, it can hinder anti-tumor T 
cell responses and bolster the population of myeloid-derived suppressor cells 
(MDSCs), thus exacerbating arginine depletion.5 Yet, inhibiting ARG o�ers 
promise by restoring arginine levels, leading to tumor regression and 
enhancing T cell functionalities.5

Targeting arginine and nitric oxide in myeloid cells could potentially 
enhance immunotherapy, but further research is needed to understand its 
impact on other immune cells. Tryptophan is another signi�cant amino acid 
being investigated for immunotherapy due to its role in cell growth and 
maintenance. Adaptive immune cell subsets such as Tregs, tolerogenic 
dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs) 
exhibit high levels of indoleamine 2,3-dioxygenase (IDO), the enzyme that 
converts tryptophan to kynurenine.5  Kynurenine has immunosuppressive 
e�ects on T cells, so targeting IDO activity could not only mitigate these 
immunosuppressive e�ects on T cells but also inhibit these adaptive 
immune cell subsets.5

Lipid metabolism has emerged as a recent target in immunotherapy. Cancer 
cells exploit lipid metabolism to support their rapid proliferation, survival, 
migration, invasion, and metastasis.26 Reprogramming lipid metabolism can 

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prevent e�ector T cell senescence, suggesting that lipid metabolism plays a 
role in regulating senescence development in T cells.27 Fatty acid metabolism 
is crucial for the di�erentiation of immune cells, and the upregulation of 
fatty acid oxidation (FAO) can enhance the functions of CD8+ T cells. 
Reprogramming fatty acid metabolism in immune cells could promote an 
inhibitory immune microenvironment.28 It is often used in combination 
therapies with other immunotherapeutic treatments, such as immune 
checkpoint blockades (ICBs).28 Recent studies have shown that targeting 
fatty acid metabolism in T cells can improve the e�cacy of ICBs. For 
instance, a study found that combining beza�brate with PD-L1 antibody 
treatment yielded better results in LLC xenograft mouse models. 
Beza�brate treatments increased the expression of FAO-related genes in 
cytotoxic T lymphocytes (CTLs), such as PGC-1α, CPT1a, and LCAD, 
and maintained the survival and function of CTLs.29

Scientists have explored manipulating iron metabolism as a strategy for 
treating tumors, given iron's crucial role in tumor proliferation. Iron 
metabolic dysfunction directly impacts cancer pathophysiology, with the 
availability of iron regulating the aggressive phenotypes of tumors.30 Many 
tumor microenvironment (TME) cells rely on iron to thrive and function 
properly. For instance, activated M2 tumor-associated macrophages (TAMs) 
can disrupt iron homeostasis within tumor cells by exporting high amounts 
of iron and increasing the production of other iron-related proteins.30 It has 
been observed that iron chelation, the bonding of ionic molecules to metal 
ions, can reverse the iron-exporting phenotype of M2 TAMs.30 Blocking 
transferrin receptor 1 (TFR1), a receptor protein that recognizes 
transferrin-bound iron, has proven e�ective in suppressing tumor growth, 
as TFR1 is often upregulated in cancer cells to enhance their iron supply.30 
Thus, cutting o� a tumor's iron supply appears to be an e�ective method to 
reduce tumor growth.

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Figure 3: The interactions between tryptophan and kynurenine. The enzyme IDO 
converts tryptophan into kynurenine, which exerts an immunosuppressive effect on T 
cells. Blocking IDO would not only eliminate the immunosuppressive effect on T cells 
but also suppress adaptive immune cell subsets, including MDSCs, Tregs, and DCs.

 4.3 Targeting Signaling Pathways

Di�erent signaling pathways, such as oxygen and nutrient sensing pathways, 
have signi�cant potential for reducing the glucose metabolism of cancer 
cells. In low-glucose environments, AMP-activated protein kinase (AMPK) 
becomes activated, and in high-glucose environments, AMPK is promoted, 
which can lead to the persistence of immunosuppressive cells.5 High levels 
of AMPK can inhibit T cells, but disabling AMPK may result in increased 
glycolysis in cancer cells. Metformin is one drug that targets AMPK by 
activating its signaling. Studies have shown that metformin reduces cancer 
risk in both mice models and humans. AMPK activation is believed to 
reduce tumor burden by slowing tumor growth, supporting the growth of 
tumor-in�ltrating lymphocytes (TILs) in the tumor microenvironment 
(TME), and blocking certain glycolytic enzymes necessary for cancer cell 

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proliferation. However, AMPK activation can also increase the number of 
immunosuppressive cells while promoting tumor regression.5 It is crucial to 
examine the e�ects on both cancer cells and the phenotypic ratios of 
immune cells.

Another crucial nutrient pathway is the mTOR pathway, which is activated 
by high levels of glucose and amino acids. In T cells, mTOR supports 
glycolysis, di�erentiation, and e�ector functions. However, because mTOR 
enhances memory formation in CD8+ T cells while low mTOR levels boost 
Treg activity, it is vital to balance mTOR levels to enhance memory 
formation without promoting Treg activity.5 Like AMPK, the mTOR 
signaling pathway has a complex nature, necessitating further research to 
develop nuanced methods that induce bene�cial immune responses without 
creating a tumor-protecting immune environment.5

Two critical targets of immunotherapy are the immune checkpoint 
pathways PD-1/PD-L1 and CTLA-4. Anti-CTLA-4 antibodies can deplete 
Treg cells from the tumor microenvironment (TME), leading to successful 
tumor rejection in animal studies.31 PD-1/PD-L1 are involved in signaling 
mediated by antigen recognition through T cell receptors.31 Antibodies that 
block the PD-1/PD-L1 checkpoint have shown signi�cant therapeutic 
e�ciency.31 These immune checkpoints mainly function by suppressing the 
metabolic reprogramming of immune cells, inhibiting glycolysis, and 
increasing lipolysis. Blocking these pathways promotes anabolic metabolic 
pathways and glycolysis, thereby restoring the e�ector function of 
tumor-in�ltrating lymphocytes (TILs). Antibodies against CTLA-4, PD-1, 
and PD-L1 reverse the glycolysis restrictions on T cells, essentially restoring 
T-cell glycolysis and interferon production.6

Another signaling pathway that has been extensively studied is the CSF-1/R 
pathway, which is expressed in myeloid cells. This pathway regulates the 
in�ltration, phenotypic and functional di�erentiation, and survival of 
myeloid cells, including tumor-associated macrophages (TAMs). Blocking 
the CSF-1/R pathway promotes the TME by facilitating the in�ltration and 
reactivation of cytotoxic T lymphocytes (CTLs).32 Consequently, studying 

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various signaling pathways can pave the way for developing nuanced cancer 
immunotherapy treatments.

As discussed, the TME consists of various components, and understanding 
these di�erences in TME is crucial for developing e�ective treatments and 
immunotherapy approaches for di�erent cancers. Identifying and targeting 
the most relevant aspects of the TME for each speci�c disease is key to 
creating successful therapies.

5. Non-small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related 
death and has become a primary focus for the development of TME-based 
immunotherapy. Similar to other cancers, NSCLC features an 
immunosuppressive tumor microenvironment (TME) and CTL 
exhaustion. However, it also has distinct characteristics such as variable 
blood �ow, areas of acidosis and hypoxia, and increased expression of 
hypoxia markers. These features can lead to metastasis and elevated 
resistance to treatment.32,33 Consequently, past therapies targeting the TME 
have focused signi�cantly on addressing hypoxia and angiogenesis.33

A recent study conducted by Zhao et al. adopts a similar strategy focusing 
on the Tumor Microenvironment (TME). The study delves into a Phase III 
trial combining bevacizumab, atezolizumab, and chemotherapy for 
metastatic non-squamous Non-Small Cell Lung Cancer (NSCLC). 
Bevacizumab, an IgG antibody that obstructs the Vascular Endothelial 
Growth Factor (VEGF) pathway by binding to VEGF-A, has demonstrated 
e�cacy in treating NSCLC. The VEGF pathway is a prime target due to its 
overexpression in NSCLC, correlating with tumor recurrence, low survival 
rates, metastasis, and mortality.

A recent study conducted by Zhao et al. adopts a similar strategy focusing 
on the Tumor Microenvironment (TME). The study delves into a Phase III 
trial combining bevacizumab, atezolizumab, and chemotherapy for 
metastatic non-squamous Non-Small Cell Lung Cancer (NSCLC). 

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Bevacizumab, an IgG antibody that obstructs the Vascular Endothelial 
Growth Factor (VEGF) pathway by binding to VEGF-A, has demonstrated 
e�cacy in treating NSCLC.19 The VEGF pathway is a prime target due to 
its overexpression in NSCLC, correlating with tumor recurrence, low 
survival rates, metastasis, and mortality.19

Apart from bevacizumab, other antibodies like ramucirumab and 
nintedanib have demonstrated enhancements in overall survival (OS), along 
with tyrosine kinase inhibitors (TKIs) capable of inhibiting the Vascular 
Endothelial Growth Factor (VEGF) pathway.19 However, the VEGF 
pathway primarily addresses the angiogenic aspect of tumors, prompting its 
utilization in combination therapies with chemotherapy and 
immunotherapy, which have proven e�ective. In a similar vein, this Phase 
III trial combines bevacizumab with atezolizumab, an immune checkpoint 
inhibitor targeting the PD-L1 ligand (anti-PD-1), alongside chemotherapy. 
This multifaceted therapeutic approach to Non-Small Cell Lung Cancer 
(NSCLC) aims to enhance progression-free survival and OS.32

5.1 NSCLC Combination Therapy

The primary treatment modality for Non-Small Cell Lung Cancer 
(NSCLC) typically involves Immune Checkpoint Inhibitors (ICIs) like 
pembrolizumab, an anti-PD-1 antibody. Pembrolizumab has emerged as the 
�rst-line treatment for metastatic NSCLC due to its notable response rates 
and sustained tumor regression.14 However, despite its e�cacy, many 
patients encounter resistance to these treatments or su�er from 
immune-related adverse events.14 Consequently, combination therapy has 
emerged as a pivotal focus for advancing cancer treatments. A recent study 
conducted in 2022 by Reckamp et al. explored combination therapy 
involving ICIs and Vascular Endothelial Growth Factor (VEGF) receptor 
inhibition in NSCLC patients. Patients were administered a combination of 
either ramucirumab (VEGF inhibitor) and pembrolizumab (ICI), or the 
investigator’s standard of care, such as docetaxel, gemcitabine, or 
pemetrexed.34 Among the 136 eligible patients, those who received 
ramucirumab and pembrolizumab exhibited signi�cantly higher overall 

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survival (OS), suggesting another promising combination therapy avenue 
for treating NSCLC.34

In September 2022, Casarrubios et al. conducted a study focusing on a 
speci�c form of combination therapy called neoadjuvant 
chemoimmunotherapy. This approach utilizes both chemotherapy and 
immunotherapy to reduce tumor size before more targeted treatment aimed 
at tumor removal. Through bulk RNA sequencing, the researchers analyzed 
samples from 41 patients with stage III Non-Small Cell Lung Cancer 
(NSCLC) who underwent three cycles of nivolumab (an anti-PD-1 drug) 
and chemotherapy. Their �ndings revealed downregulation of tumor and 
proliferation markers, along with genes associated with IFNγ signaling.35 
Additionally, they observed the regulation of numerous genes such as IFNG 
and NKG7, distinguishing between complete pathological response (CPR) 
and non-CPR tumors before and after treatment. This study lays the 
groundwork for future personalized immunotherapy approaches based on 
predictive biomarkers of CPR, in conjunction with neoadjuvant 
immunotherapy.35

5.2 Melanoma

Anti-PD-1 therapy represents a standard immunotherapy regimen for 
melanoma, a type of skin cancer. However, this treatment modality is only 
e�ective in providing long-term clinical bene�ts to approximately 40% of 
patients with advanced melanoma.36 To address this challenge, Davar et al. 
conducted a study involving the administration of pembrolizumab, an 
anti-PD-1 drug, alongside a fecal microbiota transplant (FMT) in 16 
patients with advanced melanoma who did not respond to anti-PD-1 
therapy alone.36 This combined approach of FMT and PD-1 blockade 
resulted in the reprogramming of the Tumor Microenvironment (TME), 
overcoming resistance to anti-PD-1 therapy. Notably, the treatment led to 
the upregulation of CD8+ T cells, a decrease in the percentage of naive 
CD8+ T cells, and an increase in activated and di�erentiated CD8+ T cells. 
Responders also exhibited downregulation of cytokines and chemokines 
associated with anti-PD-1 resistance, along with upregulation of biomarkers 
linked to improved outcomes.36

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A recent approach in melanoma treatment involves categorizing the Tumor 
Microenvironment (TME) to anticipate the cancer's responsiveness to 
immunotherapy. While combining di�erent Immune Checkpoint 
Inhibitors (ICIs) like anti-PD-1 and anti-CTLA-4 may appear promising, 
trials on advanced melanoma patients showed severe immune-related 
adverse events (irAEs) such as hypophysitis, pneumonitis, and thyroiditis, 
likely due to the distinct mechanisms of T cell inhibition—CTLA-4 acting 
on T cell activation, while PD-1 intervenes later.14 A recent study identi�ed 
29 functional gene expression signatures (Fges) delineating major functional 
and cellular components of melanoma tumors, classifying them into four 
subtypes: immune-enriched/�brotic (elevated angiogenesis and 
Cancer-Associated Fibroblast activation), immune-enriched/non-�brotic 
(more immune-active TME), �brotic (low lymphocyte in�ltration, high 
�broblast activity), and immune-depleted (immune-desert).37 This 
classi�cation aids in determining treatment e�ectiveness and alternative 
approaches. For instance, responses to anti-CTLA-4 treatment varied across 
subtypes, with 82% of immune-enriched subtypes responding compared to 
only 10% of �brotic subtype, suggesting appropriate utilization of ICI 
immunotherapy.37

5.3 Other Cancers (Novel Treatments/Combination Therapies)

Pancreatic cancer (PDAC) poses a signi�cant challenge for immunotherapy 
due to its low T cell in�ltration, low tumor mutational burden, and highly 
suppressive Tumor Microenvironment (TME), making it the fourth leading 
cause of cancer-related deaths.44 Combination therapy emerges as a 
promising approach, as demonstrated in a recent study by Padron et al. This 
study investigated the administration of sotigalimab and/or nivolumab 
(both anti-PD-1 drugs) alongside chemotherapy.38 The results revealed that 
combining nivolumab with chemotherapy was associated with a less 
suppressive TME, increased numbers of activated and circulating T cells, 
and achieved the primary endpoint of one-year Overall Survival (OS). 
Although sotigalimab combined with chemotherapy did not meet the OS 
endpoint, it led to greater in�ltration and di�erentiation of CD4+ cells. 
Interestingly, administering all three components together did not yield 
additional improvements.38

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Cervical cancer (CC) ranks as the fourth most prevalent cancer, with 
concurrent chemoradiotherapy (CCRT) serving as the standard 
treatment.39 However, individuals with advanced-stage disease often 
experience diminished long-term outcomes, prompting investigation into 
combination therapies. A recent study by Huang et al. in August 2022 
explored the utilization of adoptive cell therapy (ACT), a form of 
immunotherapy involving the introduction of Tumor-In�ltrating 
Lymphocytes (TILs) to evoke an immune response, following CCRT and 
its impact on survival.39 Among the 27 patients receiving ACT alone, 20 saw 
successful expansion of TILs. Subsequently, 12 patients received TILs 
post-CCRT, with 75% experiencing complete response and a disease control 
duration ranging from 9 to 22 months. Treatment-related adverse events 
were minimal, with only one patient encountering severe toxicity, 
underscoring the potential of post-CCRT ACT in managing CC.39 
E�ective combination therapy entails strategic timing of treatments. 
Another study focused on determining the optimal timing for immune 
therapy concerning CCRT revealed the bene�t of administering Immune 
Checkpoint Inhibitors (ICIs) before CCRT. This strategy capitalizes on 
maintaining tumor-speci�c immune response, as it was observed to 
diminish following CCRT. Post-CCRT, reduced numbers of Cytotoxic T 
Lymphocytes (CTLs), decreased T Cell Receptor (TCR) diversity, and 
increased Regulatory T cells (Tregs) signi�ed a weakened antitumor 
immune response.40

Researchers are investigating new treatment avenues for chronic 
lymphocytic leukemia (CLL) that focus on targeting LAG-3, a protein 
involved in inhibiting the function of natural killer (NK) cells and CD8+ T 
cells. In CLL, LAG-3 expression on leukemic cells is associated with poorer 
outcomes and decreased response to treatment.20 Relatlimab, an IgG4 
antibody that blocks LAG-3, has shown promise in preclinical studies. 
Administering relatlimab increased the proliferation of NK cells and CD8+ 
T cells without a�ecting the growth of leukemic cells. This suggests that 
LAG-3 blockade can reverse the inhibition of NK and T cells, potentially 
restoring their anti-leukemic activity. 20

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Moreover, combining relatlimab with lenalidomide, an angiogenesis 
inhibitor, led to increased T cell numbers and enhanced anti-leukemic 
activity. This combination therapy approach may o�er a synergistic e�ect in 
treating CLL by targeting both LAG-3-mediated immune suppression and 
angiogenesis. Overall, these �ndings provide a promising direction for the 
development of novel immunotherapies for CLL, particularly for patients 
who have not responded well to PD-1 or CTLA-4 blockade. 20

Cancer often spreads to the liver, complicating treatment with 
immunotherapy. Liver metastases attract activated CD8+ T cells, which 
then undergo apoptosis, resulting in a signi�cant reduction in e�ective T 
cells. 41 A study comparing patients with metastatic melanoma and NSCLC 
who received immunotherapy and targeted therapy, or immunotherapy and 
chemotherapy respectively, revealed that liver metastases were linked to 
reduced response to immunotherapy but not targeted therapy. 41 Similarly, 
in NSCLC cases, immunotherapy had limited e�cacy compared to 
chemotherapy, while radiotherapy showed promising results. These �ndings 
suggest that liver metastasis may be more e�ectively managed through non-
immunotherapeutic methods, informing future treatment strategies.41

6. Practical Applications/Discussion

Numerous innovative combination therapies extend beyond traditional 
chemotherapy and immunotherapy, delving into the modulation of the 
tumor microenvironment (TME) to bolster immune responses. For 
instance, one approach involves delivering a fecal microbiota transplant 
(FMT) via colonoscopy alongside immunotherapeutic anti-PD-1 drugs.36 
This strategy e�ectively reshapes the TME, overcoming primary resistance 
to anti-PD-1 in advanced melanoma patients. Following treatment, there's 
an increase in the proportion of CD56+CD8+T cells, indicating 
heightened circulation of active and di�erentiated CD8+ T cells.36 
Responders exhibit decreased levels of certain cytokines and chemokines 
linked to anti-PD-1 resistance, while biomarkers associated with improved 
survival are upregulated.36 Notably, variations in patient response may occur 
due to factors like tumor immunogenicity or unsuccessful colonization by 

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FMT, necessitating further investigation for its establishment as a standard 
treatment.36

Another method, as explored by Ribas et al., involves combining anti-PD-1 
therapy (speci�cally pembrolizumab) with intratumoral administration of 
an oncolytic virus, such as talimogene laherparepvec, in advanced melanoma 
patients. Initially, tumor size may transiently increase post-injection; 
however, this approach boosts CD8+ T cell in�ltration and peripheral 
CD4+ T cell presence.48 Pembrolizumab promotes the proliferation of 
CD8+ T cells, leading to a comprehensive shift in the TME and an 
augmented immune response compared to anti-PD-1 therapy alone. 
Importantly, T cells expressing PD-1 encounter tumor cells expressing 
PD-L1, a dynamic that, alongside PD-1 blockade, moderates the antitumor 
e�cacy of the administered virus.48

As previously discussed, extensive research has already been conducted on 
PD-1, PD-L1, CTLA-4, and VEGF/VEGF-A as targets for treating various 
cancers. Scientists are now focusing on identifying new potential 
biomarkers to better predict patient responses to speci�c treatments, given 
that the existing biomarkers are not perfect indicators of a patient’s response 
to immune checkpoint inhibitor (ICI) therapy.49  Vanhersecke et al. 
observed that the tertiary lymphoid structure (TLS) within tumors is 
associated with the population of CD8+ T cells. Higher TLS densities 
correspond to increased densities of CD8+ T cells. Moreover, the presence 
of more mature TLS was linked to improved survival rates, higher objective 
response rates, and longer progression-free survival. Notably, mature TLS 
emerged as the most signi�cant predictive factor for an objective response, 
independent of PD-L1 expression and CD8+ T-cell in�ltration. Patients 
with tumors containing mature TLS had better outcomes compared to 
those without mature TLS.49 Studying the TLS in tumors opens a new 
avenue for identifying biomarkers to predict patient responses to speci�c 
ICI treatments.

Two ongoing clinical trials are exploring recent advances in immunotherapy 
and tumor microenvironment (TME) mediated treatments, focusing on 
combination therapies involving LAG-3, anti-PD-1, and VEGF signaling.

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The �rst trial is investigating the e�ects of anti-LAG-3 (urelumab) alone and 
in combination with nivolumab (an anti-PD-1 drug) in patients with 
recurrent glioblastoma. The study aims to determine which treatment 
regimen is more e�ective at killing tumor cells. Currently, 63 patients are 
enrolled, and the trial is expected to conclude by November 2023.50

The second trial, entering phase II, is evaluating the e�cacy and safety of a 
combination of anti-PD-L1/VEGF drugs with traditional chemotherapy in 
treating non-small cell lung cancer (NSCLC). The primary objectives are to 
measure the objective response rate to the treatment and progression-free 
survival, which involves monitoring the time from the start of treatment 
until the cancer progresses or the patient dies from any cause.51

Other monitored outcomes include overall survival rate, disease control, 
response duration, treatment-related adverse events, and the correlation 
between PD-L1 expression and antitumor e�ect. The clinical trial aims to 
enroll 374 patients and is expected to be completed by December 2025.51

7. Conclusion

The tumor microenvironment (TME) is a promising target in 
immunotherapy. Due to its variability and adaptability, further research is 
needed to e�ectively target di�erent TME components. Current techniques 
include immune checkpoint blockades like PD-1 and CTLA-4, and 
targeting lactic acid and metabolism. Future prospects lie in combination 
therapies with chemotherapy or neoadjuvant therapy, microbiota fecal 
transplants to enhance TME for therapy, classifying CPR versus non-CPR 
tumors, and optimizing the timing of immunotherapy in combination 
treatments.36

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