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96 The Dynamics of Tumor Microenvironment and Therapeutic Targets
5.2.1.3.2 Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)
GM-CSF responsible for expansion and activation of granulocytes and macrophage
can induce proliferation, maturation, and survival of DCs. Several strategies under
investigation are in phase Iand phase II trials. GM-CSF is being tried as an adju-
vant therapy via systemic administration, as intratumoral monotherapy by direct
injection in metastatic lesions, in combination with chemotherapy or with ICI, or
as GM-CSF–secreting vaccines (NCT02703714, NCT01134614, NCT02977156,
and NCT00317603). Administration of GM-CSF as monotherapy in patients with
melanoma increased mature DCs, and improved the overall survival (OS) by 60% in
comparison with matched controls in early clinical trials (Lynch et al. 2012; Spitler
et al. 2009).
5.2.1.3.3 Dendritic Cell (DC) Vaccines
Patient-derived DCs are injected ex vivo to modulate many properties of DCs.
Monocytes and hematopoietic stem and progenitor cells (HSPC) from the blood are
isolated and grown in cell culture with recombinant cytokines to promote differ-
entiation. Immature DCs are then matured and pulsed with TAAs and diverse DC
maturation cocktails are added for stimulating maturation. DC vaccines increase
the DC presentation capacity for specic TAAs, increase migration to lymph nodes,
overcome tumor immunosuppression, and promote recruitment of lymphocytes, NK
cells, and supplementary DCs (Perez and De Palma 2019). DC vaccines showed
increase in antigen-specic T and B cell activity and accumulation of CD8+ CTLs
into the TME. Clinical response like CR and PR also seen with no toxicity in clini-
cal trials but to date have not been translated in to therapeutic success (Zhang et al.
2018). Currently, combination of DC vaccines with ICIs and chemotherapy is being
evaluated (NCT04567069, NCT04201873, and NCT03092453).
5.2.1.4 Tumor-Associated T Cells
Currently, two strategies are being employed to harness the antitumor activity of T
cells: (i) inhibition of immune checkpoint inhibitors and (ii) adoptive T cell therapy.
5.2.1.4.1 Immune Checkpoint Inhibitors
5. 2.1.4.1.1 Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4) Inhibitors They
are expressed by T cells and bind to B7-1/B7-2 costimulatory molecules on APCs—a
negative regulator of T cell activation. It was hypothesized that inhibition of CTLA4
could induce a long lasting immunologic memory. Ipilimumab (mAb blocking CTLA4)
was approved for melanoma by FDA in 2011. But the therapeutic response has not been
encouraging in in NSCLC, small-cell lung cancer (SCLC) and prostate cancer (Kwon
et al. 2014; Lynch et al. 2012; Reck et al. 2013).
5.2.1.4.1.2 PD-1/PD-L1 Axis Inhibitors PD-1 (programmed cell death protein1)
and its ligand PD-L1 binding can mediate T cell apoptosis, pro-inammatory cyto-
kine production and cause T cell exhaustion (Wei et al. 2017). Pembrolizumab and
nivolumab were the rst FDA-approved PD-1-targeted immunotherapies for patients
with melanoma in 2014 (Robert et al. 2015). Pembrolizumab has also been approved
97Therapeutic Interventions in Modulating Tumor Microenvironment
for the treatment of PD-L1-expressing NSCLC, urothelial carcinoma, and head and
neck squamous cell cancer. Atezolizumab mAb against PDL1 was rst approved
in 2016 for urothelial carcinoma and later for patients with NSCLC, triple-negative
breast cancer, and SCLC, because of better efcacy and lower toxicity compared to
docetaxel (Rittmeyer et al. 2017; Rosenberg et al. 2016). Two other mAbs against
PDL1, avelumab and durvalumab are used for treatment of urothelial carcinoma,
advanced renal cell carcinoma, and NSCLC (Antonia et al. 2017; Motzer et al. 2019).
5.2.1.4.1.3 Lymphocyte Activation Gene (LAG3) Inhibitors LAG3 is expressed
by activated CD4+ and CD8+ T cells, Tregs, and subsets of NK cells, B cells, and
pDCs. LAG3 is structurally similar with the CD4 receptor. MHC II binds to LAG3
with a higher afnity than CD4 (Andrews et al. 2017). LAG3 signaling is a negative
regulator of T cell activation, proliferation, and cytokine production and associated
with a poor prognosis in breast cancers, NSCLC, and renal cell carcinoma. Many
compounds targeting LAG3-MHC II interaction (e.g., LAG525, relatlimab, IMP321,
and IMP761 are now undergoing phase I or II trials either as monotherapy or in
combination, predominantly with anti-PD-1- or anti-PD-L1-neutralizing antibodies
(NCT03459222, NCT03642067, and NCT02460224). Aphase II/III study evaluated
combination therapy with nivolumab and relatlimab vs. nivolumab alone in unre-
sectable primary melanoma or metastatic melanoma. The inhibition of two immune
checkpoints, LAG-3 and PD-1, provided a greater benet (progression-free survival)
than inhibition of PD-1 alone (Tawbi et al. 2022).
5.2.1.4.1.4 T Cell Immunoglobulin and Mucin-Domain-3 (TIM-3) Inhibitors TIM-3
plays a key role in inhibiting Th1 responses and the expression of cytokines, such as
TNF and INF-γ. Ligands for TIM-3 include galectin-9, high-mobility group protein B1
(HMGB1), carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), and phos-
phatidyl serine (PtdSer). TIM-3 and its ligand binding cause negative T cell response
and T cell apoptosis. An increased TIM-3 is associated with poor prognosis (Zhang
et al. 2017). Several TIM-3 antagonist antibodies, including TSR-022, cobolimab,
MBG453, and Sym023, are being currently evaluated. TSR-022 was well tolerated in
patients with anti-PD-1–refractory NSCLC and melanoma, and combination therapy
with anti-PD-1 resulted in an ORR of 15% and stable disease in 40% of patients.
5.2.1.4.1.5 T Cell Immunoglobulin and ITIM Domain (TIGIT) Inhibitors TIGIT
is expressed by NK cells and T cells, and its main ligand is CD155, expressed by both
APCs and tumor cells. It acts as a negative regulator of NK cell and T cell func-
tions. TIGIT may also act by interfering with the costimulatory molecule DNAM1 or
by directly initiating an inhibitory signaling cascade (Cui and Elkord 2024). TIGIT
upregulation is seen in several tumor types, and its expression is correlated with poor
clinical outcomes in melanoma and acute myeloid leukemia (Fourcade et al. 2018;
Kong et al. 2016). Various anti-TIGIT antibodies, including tiragolumab, AB154,
and BMS-986207 are being evaluated in phase I/II either alone or in combination
with other immunotherapies (NCT03628677, NCT02913313, and NCT04300647).
Tiragolumab has been granted FDA Breakthrough Therapy Designation (BTD)
98 The Dynamics of Tumor Microenvironment and Therapeutic Targets
in combination with atezolizumab for PD-L1-high NSCLC based on the positive
results of the CITYSCAPE phase II clinical trial (NCT03563716). The phase III
SKYSCRAPER-01 study (NCT04294810) evaluating the addition of tiragolumab to
atezolizumab as rst-line treatment for people with PD-L1-high, locally advanced, or
metastatic non-small-cell lung cancer (NSCLC) did not meet its co-primary endpoint
of progression-free survival (PFS).
5.2.1.4.1.6 Adoptive T Cell Therapy It’s a form of transfusion therapy in which
mature T cell subsets (tumor-inltrating lymphocytes [TILs]) are isolated from sur-
gically excised samples and then subsequently expanded and reinfused into patients.
After initial success in preclinical studies, ACT of TILs, together with IL2, was eval-
uated in patients with metastatic melanoma. Although tumor regression was reported
in approximately one-third of the patients, the duration of response lasted only four
months on average, and few patients showed a CR (Lowery et al. 2025; Palomero
et al. 2025; Sarnaik et al. 2021). The success of TIL therapy depends on the presence
of functional effector T cells with antitumor activity, which not seen in most cancer
types, and the activation and expansion of these cells in culture can be technically
difcult (Zhao and Cao 2019). So strategies to genetically modify T cells have been
developed, including TCR and CAR T cell therapies. They manipulate a patient’s
own T cells ex vivo to express receptors that recognize tumor-specic antigens and
reintroduce them to boost T-cell-mediated cancer cell killing. Though TCR-T cell
therapy was found successful in preclinical and clinical studies to date, there is no
FDA approved one for the same. TIL and TCR T cell therapies can target only cancer
cells that present their antigens via MHC/HLA. But CAR (chimeric antigen receptor)
T cells can recognize target molecules on the surface of tumor cells (Waldman, Fritz,
and Lenardo 2020). CAR T cell therapy has proved extremely successful for hema-
tologic malignancies. CAR T cell therapies directed toward CD19 for the treatment
of B cell acute lymphoblastic leukemia (tisagenlecleucel), large B cell lymphoma
(axicabtagene ciloleucel), and mantle cell lymphoma (brexucabtagene autoleucel)
have been approved by FDA. Several CAR T cell therapies are now being evalu-
ated in clinical trials for the treatment of other subtypes of lymphoma, leukemia,
and multiple myeloma (Zhao and Cao 2019). But CAR T cell therapies were found
to be moderately effective for solid tumors, including neuroblastoma, due to more
complex TMEs and heterogeneity (Park et al. 2007). Anewer modied approach,
armored CAR T cell therapy, utilizes armored T cells, which constitutively express
cytokines or ligands (like IL12), which overcome immunosuppression mediated by
Tregs and myeloid cells in the TME, promote CD8+ T cell cytolytic activity, and
enhance myeloid cell recruitment and antigen presentation (Chmielewski et al. 2011).
5.2.1.4.1.7 The Gut Microbiome The role of gastrointestinal microbiota in
cancer development and response to therapy has gained signicant importance
recently for their role in therapeutic response and their protection against toxic-
ity of several rst-line and novel therapies (Finlay et al. 2020). Certain gut micro-
biota are associated with better response to immune checkpoint inhibitors, higher
immune cell inltration into tumors, and enhanced systemic immunity (Frankel et
al. 2017). Microbiome-targeting therapies combined with conventional and novel
99Therapeutic Interventions in Modulating Tumor Microenvironment
immunotherapies are evaluated in number of clinical trials (Finlay et al. 2020).
Aphase Iclinical trial in patients with immunotherapy-refractory melanoma recently
reported favorable responses when combined fecal microbiota transplantation with
reinduction of anti-PD-1 therapy (Davar et al. 2021).
5.2.2 therapies direCted toward the tumor-assoCiated vasCulature
Due to several morphologic and functional changes, the tumor vasculature becomes
tortuous and dysfunctional and exhibits a heterogeneous vascular permeability. This
aberrant vasculature can result in inefcient delivery of oxygen, leading to creation
of a hypoxic environment associated with increased cancer aggressiveness (Schito
and Rey 2020). These dysfunctional vessels can selectively block the inltration of
specic immune cell types and signicantly interfere with the delivery and distribu-
tion of therapeutic agents (Haibe et al. 2020). Hence, the following strategies are
employed.
5.2.2.1 Antiangiogenic Therapies
Several soluble growth factors, including members of the VEGF, PDGF, EGF, FGF2,
and ANG families, favor increased angiogenesis. VEGFA/VEGFR2 signaling has
been most widely used for antiangiogenic cancer therapy. Bevacizumab, a human-
ized anti-VEGFA mAb, was the rst to be approved for several cancers, including
metastatic colorectal cancer, cervical cancer, NSCLC, glioblastoma, and metastatic
renal cell cancer. Most of the ongoing trials are on assessing the combination of
anti-VEGF therapy with chemotherapeutic agents or immunotherapies (Duru, van
Egmond, and Heemskerk 2020). In BEATRICE (phase III) trial for triple negative
breast cancer, the combination of bevacizumab with anthracyclines and/or taxanes
showed no difference in overall survival (Bell et al. 2017).
Tyrosine kinase inhibitors (TKI) targeting VEGF, FGF, and PDGF receptors are
the second line antiangiogenic drugs. Many of these compounds like pazopanib,
sorafenib, and sunitinib have showed better results in clinical trials as monothera-
pies, maybe because they not only target the vasculature but also block multiple
dysregulated pathways in cancer cells (Yamaoka et al. 2018). Additional antian-
giogenic strategies include the use of ANG2–TIE2 inhibitors, such as trebananib,
MEDI3617, and rebastinib, which are now undergoing clinical evaluation (Gillen,
Richardson, and Moore 2019). However, phase III trials testing the combination of
trebananib with carboplatin and paclitaxel failed to show clinical benet in ovarian
cancer (Vergote et al. 2019). Several direct inhibitors of endothelial cells, such as
endostatin, are also being evaluated in clinical trials in combination with platinum
based compounds (Li et al. 2019; Sun et al. 2016).
The possible resistant mechanisms accounting for the less than optimum results
could be due to hypoxia and increased invasiveness and metastasis of cancer cells
with high dose antiangiogenic therapies (Paez-Ribes et al. 2009). Careful dosing of
antiangiogenic therapies could favor vessel normalization, to provide better patient
outcomes. Since continuous inhibition of VEGFA can lead to the compensatory
upregulation of other angiogenic factors, different strategies are employed for ves-
sel normalization. Adual inhibitor of VEGFA and ANG2 (A2V or vanucizumab)
100 The Dynamics of Tumor Microenvironment and Therapeutic Targets
improved vessel normalization in preclinical models, which is being evaluated in
clinical trials (Hidalgo et al. 2018). Other vessel normalization strategies have been
evaluated in preclinical studies include the re-expression of specic semaphorin
family members, endogenous antiangiogenic molecules that are frequently down-
regulated in tumors and the inhibition of regulator of G protein (RGS5) signaling
(Hamzah et al. 2008; Iragavarapu-Charyulu, Wojcikiewicz, and Urdaneta 2020).
5.2.2.2 Combining Vascular-Targeted Therapies with Immuno-Therapies
The tumor vascular networks (blood and lymphatic) can modulate the inltration of
different immune cell populations into tumors through many ways. The inltration
of cytotoxic T lymphocytes (CTLs) via the blood vasculature may be induced by
the deregulation of cell adhesion molecules such as intercellular adhesion molecule
1 (ICAM1) and vascular adhesion molecule 1 (VCAM1). T cell suppression occurs
by expression of inhibitory receptors and molecules. Endothelial cells produce Fas
ligand (FasL), causing induction of T cell death (Schaaf, Garg, and Agostinis 2018).
Other immune cell types, including Tregs, monocytes, and neutrophils, can freely
cross the tumor vasculature (Joyce and Fearon 2015). So a new strategy of combin-
ing antiangiogenic therapies with vaccines, cell therapies, or ICI strategies is being
employed (Fukumura et al. 2018). In a phase III trial, the combination of axinitnib
(VEGFR TKI) and pembrolizumab (anti-PD-1) showed in increased OS, ORR, and
PFS compared with sunitinib treatment alone in patients with advanced renal cell
carcinoma (Rini et al. 2019).
Tumor-associated lymphatic vessels are emerging as complex multifaceted reg-
ulators of cancer immunity (Garnier, Gkountidi, and Hugues 2019). Lymphatic-
mediated transport of tumor antigens by DCs is central to the generation of antitumor
immunity (Fransen et al. 2018). Intra tumoral accumulation of CD8+ T cells has
been observed in murine melanoma models and in colorectal cancer and melanoma
patient samples (Fankhauser et al. 2017; Mlecnik et al. 2016). Tumor-associated lym-
phatic endothelial cells can also display an immunosuppressive prole and express
PD-L1 thus limiting DC maturation and the cytotoxic function of T cells (80).
Metastatic cells can also disseminate through lymphatic vessels. So new strategies
are formulated to selectively boost lymphatic vessel network’s immune-modulatory
functions to enhance efcient responses to immune-based therapies and potentiate
antitumor immunity.
5.2.2.3 Improving Drug Penetration
Though certain features of the tumor vasculature like heterogeneous permeability,
leakiness, and reduced tight junctions may be expected to enhance drug penetration
into the tumors, in reality this leaky vasculature results in poor delivery of both
oxygen and antitumor agents. This aberrant vasculature can also increase interstitial
uid pressure (IFP), further decreasing the delivery of drugs. So vascular normaliza-
tion is being employed as a new strategy to overcome the barrier. Cediranib, a pan-
VEGFR TKI, showed improved tumor blood perfusion and vessel normalization in
patients with glioblastoma in phase II trials (Batchelor et al. 2007). Similarly, a sin-
gle infusion with bevacizumab decreased IFP, tumor perfusion, and microvascular
density in human colorectal cancer (Willett et al. 2004). Other strategies to improve
101Therapeutic Interventions in Modulating Tumor Microenvironment
drug delivery include the use of nanoparticles, liposomes, antibody–drug conjugates,
and ultrasound-mediated techniques (Tharkar et al. 2019; Zhao et al. 2024).
5.2.3 therapies direCted agaiNst extraCellular matrix aNd tumor stroma
5.2.3.1 Extracellular Matrix (ECM)
The extracellular matrix is composed of collagens, glycoproteins, elastin, bronec-
tins, and proteoglycans, which are secreted by cells into the extracellular space.
The ECM not only provides structural support but also plays an important role in
regulating the behavior of cancer and TME cells. For example, increasing stiff-
ness in the surrounding tissue can promote the epithelial to mesenchymal transi-
tion in cancer cells, associated with tumor invasiveness, stemness, and metastasis
(Henke, Nandigama, and Ergun 2019; Kai, Drain, and Weaver 2019). The aberrant
accumulation of ECM acts as a physical barrier for therapeutic agents and induces
the activation of integrin and focal adhesion kinase (FAK) signaling, which leads
to reduced apoptosis, increased pro-survival signaling, and chemoresistance (Diaz
Osterman et al. 2019). Certain genes, such as desmoplakin or SPARCL1 by ECM
remodeling, can induce resistance to chemotherapy resulting poor prognosis (Riaz
et al. 2012).
Novel ECM-targeting therapies are being explored like using collagenases or hyal-
uronidases to degrade the different components of the ECM for enhanced distribution of
therapeutic drugs. Arandomized phase III trial of pegvorhyaluronidase alfa (PEGPH20)
with nab-paclitaxel plus gemcitabine for patients with hyaluronan-high metastatic
pancreatic ductal adenocarcinoma increased the ORR but did not improve OS or PFS
(Doherty, Tempero, and Corrie 2018). Similarly, a phase IB/II clinical trial in patients
with metastatic pancreatic adenocarcinoma showed increased toxicity and adverse
effects when combining FOLFIRINOX with PEGPH20 (Ramanathan et al. 2019).
Other strategies involve decreasing the de novo synthesis of ECM. This can be
achieved by blocking the key signaling pathways that promote ECM production, such
as TGFβ or HIF1α, or by inhibiting the modifying enzymes necessary for the pro-
duction, secretion, and maturation of the different ECM components. Simtuzumab,
an antibody targeting LOXL2 (lysyl oxidase), was evaluated in a phase II trial in
combination with gemcitabine and FOLFIRINOX in patients with colorectal can-
cer and pancreatic cancer, respectively, but could not produce better clinical out-
come (Benson et al. 2017; Hecht et al. 2017). Drugs with antibrotic properties,
such as losartan, metformin, and pirfenidone, are also being repurposed. Losartan
showed clinical benets in phase II trials in combination with FOLFIRINOX and
chemoradiotherapy with uorouracil or capecitabine in pancreatic cancer (Murphy
et al. 2019). In another strategy targeting integrins or the downstream effector focal
adhesion kinase (FAK) is being explored to modulate integrin-mediated signaling.
FAK inhibitor defactinib was tested in phase II clinical trials, but the combination
of defactinib with rst-line chemotherapy failed to show clinical benets in patients
with malignant pleural mesothelioma (Fennell et al. 2019).
So far, the strategies employed to target ECM have not been successful. The ECM
is highly complex and formed by various components and regulated by multiple path-
ways and the therapies produce many off-target effects like toxicities and secondary
102 The Dynamics of Tumor Microenvironment and Therapeutic Targets
adverse effects (Wang-Gillam 2019). The future of ECM-directed therapies will
depend on identifying rational combinations with other treatment modalities.
5.2.3.2 Cancer-Associated Fibroblasts (CAFs)
CAFs not only deposit ECM but also produce matrix remodeling enzymes that pro-
mote tumor invasion, metastasis, and resistance to therapies. CAFs also promote
tumor growth and invasion by secreting several cytokines, exosomes, and growth
factors, for example, leukemia inhibitory factor (LIF) and growth differentiation fac-
tor 15 (GDF15) (Bhome et al. 2017; Bruzzese et al. 2014; Shi et al. 2019). Secretome
of CAF besides affecting tumor cell function also inuences the vasculature (VEGF)
and immune cells (cytokines).
One strategy to modulate CAF is broblast activation protein (FAP). FAP-
expressing CAFs have been associated with immunosuppression in several pre-
clinical models and in human samples (Kieffer et al. 2020). Several phase I and
II trials (NCT02198274, NCT02627274, and NCT03386721) are evaluating FAP-
targeting agents (PT630, RO6874281, and sibrotuzumab) in different solid tumors
like colorectal cancer. Other signaling pathways of CAF activation like Hedgehog,
NFκB, CXCR4, FGFR, or TGFβ and specic inhibitors of these pathways are also
being studied in clinical trials (Sahai et al. 2020). But a phase II trial combining a
Hedgehog inhibitor (vismodegib) with gemcitabine showed a worse clinical outcome
than that with gemcitabine alone (De Jesus-Acosta et al. 2020). This shows that
CAFs can have both protumorigenic and antitumorigenic effects. Thus, alternative
strategies to modulate CAF have been investigated, such as CAF reprogramming
or CAF normalization by vitamin D or vitamin A. Treatment of pancreatic cancer
preclinical models with a vitamin D analogue induced CAF reversion to stellate cells
and improved antitumor efcacy (Sherman et al. 2014). The vitamin D analogue
paricalcitol with gemcitabine and nab-paclitaxel is now undergoing phase Iand II tri-
als in metastatic pancreatic adenocarcinoma (NCT03520790) and paricalcitol alone
in metastatic breast carcinoma (NCT00637897).
The biology of the CAF is complex and still remains to be known properly. CAFs
are high heterogenous and can switch between different phenotypes (Sahai et al.
2020). When a population of CAFs positive for CD10 and GPR77 was specically
targeted, it increased sensitivity to chemotherapy in breast cancer models (Su et al.
2018). It has also been reported that changes in the lipid metabolism of aged bro-
blasts contribute to therapy resistance in melanoma (Alicea et al. 2020). Ahigher
prevalence of somatic copy-number alterations in CAFs isolated from colorectal can-
cer patient samples were found as compared with broblasts isolated from normal
adjacent tissue (Zhou et al. 2020), making therapeutic targeting of CAFs if geneti-
cally unstable. So proling and targeting of CAF remains a challenge to develop
strategies to harness them for successful therapeutic benet.
5.3 DISCUSSION
The modulation of the TME has given a whole new paradigm in cancer therapy and
is being viewed as a promising strategy in the anticancer armamentarium. Many
drugs and cell-based therapies directed toward the blood vasculature, immune
103Therapeutic Interventions in Modulating Tumor Microenvironment
checkpoints, and T cells have been approved for treatment of various cancers and
there is a continued exploration additional TME targets to exploit. In this chapter, we
have tried to highlight some examples of the success of TME therapies, as well as
some therapeutic failures. Nevertheless the eld of TME will inevitably continue to
focus on developing novel strategies to overcome immunosuppressive mechanisms,
to activate antitumor immunity and/or boost the efcacy of immune-targeted agents.
Immune suppression is mediated via multitude of complex mechanisms involv-
ing cells which are interconnected. Hence, strategies to identify and selectively
target key vulnerabilities is the key to success. One such example is modulation
of the tumor vascular microenvironment in combination with immunotherapies. In
preclinical model of glioblastoma, CAR-T cells engineered to target the epider-
mal growth factor receptor variant III (EGFR vIII) mutation in glioma cells were
given along with inhibitors of the p21-activated kinase 4 (PAK4) enzyme selectively
expressed in glioblastoma blood vessels (Ma et al. 2021). This therapy caused repro-
gramming of the vasculature promoting immune cell adhesion and enabled CAR-T
cells to enter the brain resulting a robust antitumor response. Another example is
desmoplastic colorectal carcinoma with poor prognosis and resistance to chemother-
apy (5-FU and cisplatin). In genetic Apc-mutant mouse models (CRC), the expres-
sion of the transcription factor prospero homeobox 1 (PROX1) was found reduced.
Loss of PROX1 promoted the growth of desmoplastic, angiogenic, and immunologi-
cally silent tumors through activation of MMP14. Although chemotherapy inhib-
ited PROX1-procient tumors, it promoted further stromal activation, angiogenesis,
and invasion in PROX1-decient tumors. So when blockade of vascular endothelial
growth factor A(VEGFA) and angiopoietin-2 (ANGPT2) was given in combination
with CD40 agonistic antibodies it promoted antiangiogenic and immunostimulatory
reprogramming of PROX1-decient tumors, destroyed tumor brosis, and enhanced
T cell-mediated killing of cancer cells (Ragusa et al. 2020). These two are bright
examples of planning successful preclinical models with complex multitargeting
strategies to modulate the TME, which can guide to plan immunotherapy clinical
trials.
Rational stratication of patients in advance and accurate monitoring of the
immune response and other parameters while on trial are important so as to gain
as much dynamic information as possible for responders versus non-responders. For
example, non-invasive liquid biopsies routinely used to measure circulating tumor
DNA in the blood was recently combined with peripheral immune analyses to predict
clinical benet from immune checkpoint inhibitors in patients with NSCLC while on
treatment (Ai et al. 2024). Extracellular vesicles (EVs) are small, lipid-bound par-
ticles containing nucleic acid and protein cargo, which are excreted from cells under
a variety of normal and pathological conditions, including cancer (Lane et al. 2018).
EVs are now increasingly used as diagnostic markers because of highly accessibil-
ity (found in nearly all body uids), and they provide relevant information about the
pathologic state like tumor stage, response to therapy, and tumor microenvironment
(Welsh et al. 2024). Several trials are evaluating EVs as biomarkers. In some planned
studies, the tumor immune microenvironment is being assessed in biopsy samples
collected before treatment, after the rst cycle of neoadjuvant chemotherapy, and at
the time of surgery (Park et al. 2020).
104 The Dynamics of Tumor Microenvironment and Therapeutic Targets
The TME can differ from one organ to another, so it’s not prudent to extrapolate
ndings between different tumor types. Moreover, the patient should be treated as a
whole, not only the tumor, because systemic inuences—for example, the gastrointesti-
nal microbiome, metabolism, diet, age, and physical conditions—can alter the TME and
affect treatment response. Continued investigation into the TME as a comprehensive
system by analyzing and integrating all TME components will reveal further exciting
insights into the TME in the future. Knowledge of the complex dynamic interactions in
the TME holds the key to formulate novel strategies for successful cancer therapy.
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