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36 The Dynamics of Tumor Microenvironment and Therapeutic Targets
early MDSCs (E-MDSCs; CD13
−
CD14
−
CD33
+
), monocyte MDSCs (Mo-MDSCs;
CD11b
+
LY6C
hi
LY6G
−
), and polymorphonuclear MDSCs (PMN-MDSCs; CD11b
+
LY6C
lo
LY6G
+
) (Bronte et al. 2016). Only Mo-MDSCs and PMN-MDSCs are found in
the TME and exhibit enhanced inhibitory phenotypes as well as strong immunosup-
pressive potential compared with E-MDSCs. MDSCs produce immunosuppressive
IDO, ROS, arginase, and NO and prevent antitumor functions of T cells by block-
ing IL-2-mediated signals and NK cells by directing the secretion of IL-10, thereby
increasing the effects of Tregs (by secreting IL-10 and TGF-β) (Kolahian et al. 2016;
Kusmartsev et al. 2004; Y. Liu et al. 2003; Mazzoni et al. 2002). Otherwise, MDSCs
also contribute to the tumor development by creating a premetastatic niche, promot-
ing the neovascular invasion, angiogenesis, and tumor cell growth.
Targeting immune-suppressing effects of MDSCs is another promising immuno-
therapeutic approach. These strategies are divided into four major categories: (a) the
MDSC differentiation into mature myeloid cells, (b) reducing the number of MDSCs,
(c) preventing the development of MDSCs, and (d) shifting immunosuppression cre-
ated by MDSCs. MDSCs can be differentiated into mature myeloid cells by a drug
named as all-trans retinoic acid (ATRA) (Iclozan et al. 2013; Nefedova et al. 2007).
Additionally, there are various chemotherapeutic agents, such as paclitaxel, cispla-
tin, 5-uorouracil (5FU), gemcitabine, and tyrosine kinase inhibitors (TKIs), target-
ing against VEGF, c-KIT, and STAT-3, that deplete MDSCs and enhance antitumor
activities of T cells (Eriksson et al. 2016; Ko et al. 2009). Immunosuppressive activ-
ity of the MDSCs is inactivated by targeting prostaglandin E2 (PGE2)/cyclooxygen-
ase 2 (COX-2) axis signaling. This approach reduces the recruitment of MDSCs,
their differentiation and inhibit the production of the MDSCs related inhibitors (ROS
and arginase-1), thus controlling the tumor progression. Arecent study on glioblas-
toma identied early-stage myeloid-derived suppressor cells (E-MDSCs) as a highly
proliferative, hypoxic, and metabolically active population. These cells appear to
accumulate around a “stem-like” tumor subpopulation, establishing an FGF11–
FGFR1 interaction within the TME that suppresses T cell proliferation (Marvel and
Gabrilovich 2015). Tumor-associated neutrophils (TANs) is also a key player in
TME remodeling. TANs can secrete factors that promote epithelial-mesenchymal
transition (EMT) and affect T cell inltration (Giram et al. 2025; S. Li et al. 2025).
2.4 ADAPTIVE IMMUNITY NETWORKS IN THE TIME
Tumor-educated innate immune cells often adopt immunosuppressive phenotypes
that inhibit adaptive immune responses. Adaptive immune cells play critical role
in reprogramming the TME in favor of arrays of functions, such as tumor develop-
ment, progression, or control (Schreiber et al. 2021; X. Yang et al. 2014). Adaptive
immune cells are considered an excellence therapeutic targets and tools for precision,
e.g., ICI, or CAR-T cells, respectively (Du et al. 2025; Huang et al. 2024). Cell-
mediated immunity is a subtype of adaptive immunity, dependent on the interaction
between innate and adaptive immune cells, and can either promote or suppress T cell
responses, and it is governed by multiple subpopulations of T cells. CD8
+
cytotoxic
T cells secrete granzyme and perforin and detect abnormal tumor antigens, followed
by proliferating and targeting cancer cells for destruction, thereby associated with
37Shaping Cancer
positive prognosis. CD4
+
T helper cells coordinate immune responses, with Th1
cells supporting antitumor activity and Tregs (canonically CD4
+
T cells) promot-
ing tumor development (Johnson et al. 2025). Exhausted T cells (Tex) are dened
by expressing some inhibitory receptors (PD1, Tim-3, CTLA-4, etc.), transcrip-
tion and signaling factors, and the downregulation of key effector molecules (Nair
et al. 2025). Additionally, innate immune cells, such as DCs, TAMs, NK, and neutro-
phils, can alter the TME in ways that affect adaptive immune cell function. Mature
DCs expressing co-stimulatory molecules CD40, CD80, CD86, and activate T cells
(L. Wang et al. 2022). Immature or suppressive DCs induce T cell tolerance by
downregulating antigen presentation capacity and upregulating inhibitory molecules
like PD-L1 (Baumjohann and Ansel 2013). Polarization of macrophages toward M2
phenotype and the accumulation of MDSCs is associated with activation of immune
suppressive adaptive immune responses (Groom 2019; S. J. Xu et al. 2023). Targeting
innate immune cells in combination with adaptive immune cell-focused therapies
(e.g. checkpoints, PDL/PDL1 or CTL4 inhibitors) shows promise in overcoming
resistance to immunotherapy and enhancing overall efcacy (Baumjohann and
Ansel 2013). For instance, strategies either to target PDL/PDL1 or CTL4 expressing
immune cells or to reprogram tumor-associated macrophages (TAMs) from an M2 to
an M1 phenotype can enhance T cell-mediated antitumor responses. The core mem-
bers of the adaptive immunity are the Th cells that provide defense against invasion
of malignant cells by secreting specic kinds of cytokines (S. J. Xu et al. 2023). These
cytokines further help in attracting or inducing other immune cells such as cytotoxic
CD8+ T cells and antibody-producing B cells activation and differentiation. While
stem-like CD62L
+
CD8
+
T cells induce antitumor immune responses (Ruan et al.
2025). Afew microRNAs (miRNAs) are responsible for Th cell regulation, focusing
on the activation, development, and tumor immunity (S. J. Xu et al. 2023).
Th cells help in regulating the humoral and cellular immune responses to a wide
range of cancer cells or pathogens and helps in determining the success of vaccine
production. Th cells originate from the hematopoietic stem cells (HSC) in the bone
marrow and undergo T cell commitment, β-selection, and positive/negative selec-
tion stages to generate single-positive CD4+ cells (Hosokawa and Rothenberg 2021).
Generally, native CD4+ T cells remain quiescent and inactive, which upon antigen
recognition and co-stimulation gets activated and differentiate into various effector
T cells (Teff cells) to eliminate tumor cells or pathogens. During the whole process,
the CD4+ T cells differentiate into the helper Th cells, which include Th1, Th2,
Th17, T follicular helper cells (Tfh cells), and other induced regulatory T cells (iTreg
cells). At death stage, most of the Th cells die, while the remaining ones, which
are smaller in number, survive to differentiate into memory T cells and are distrib-
uted in tissue, providing an automatic pervasive network for immunosurveillance
(Seo, Lee, and Son 2025). Certain subtypes of Th cells and their numbers within the
TIME strongly impacts the tumor immunity, which is precisely regulated by certain
important factors, including cytokines, perforins, granzymes, and chemokines. T
cell immunoglobulin and mucin domain-3 (TIM-3) expression has also been linked
T cell exhaustions, poor prognosis, and survival (Chaudhary et al. 2025).
The second population of the adaptive immune cells that are found in the TME
are B cells (X. Wu et al. 2025). The multifaceted roles and heterogeneity of B
38 The Dynamics of Tumor Microenvironment and Therapeutic Targets
cells add complexity to their characterization and pose signicant challenges in the
development of effective therapeutic strategies. B cells, along with other immune
cell populations, aggregate within the tumor microenvironment to form tertiary
lymphoid structures (TLS), which serve as sites of localized immune activation and
provide critical insights into tumor immunobiology. The development of therapeu-
tic strategies targeting B cells, antibody responses, and TLS represents a promising
avenue for advancing cancer immunotherapy. Over almost two decades, quite a few
studies have shown the protumorigenic properties of the B cells (Downs-Canner
et al. 2022; Y. Liu, Zhou, and Wang 2021; H. Yang et al. 2024). Asubstantial
body of research has demonstrated that the presence of B cells, identied through
cellular or genomic methodologies, is associated with improved clinical out-
comes in cancer patients. Despite these ndings, the role of B cells as biomarkers,
either as key effector cells or indicators of a productive immune response remains
insufciently dened (Largeot et al. 2019). In both animal and mouse models, B
cells have been associated with poor clinical outcomes and impaired antitumor
immunity, mostly with regards to the generation of immunosuppressive cytokines.
Future research will aim to provide a clearer understanding of the role of adaptive
immunity in establishing the TIME that can suppress immune responses relevant
to cancer progression.
2.5 DISCUSSIONS
The dynamic interactions between tumor cells and both innate and adaptive immune
cells within the tumor microenvironment (TME) are crucial in shaping cancer
evolution and determining responses to chemotherapeutic and immunotherapeutic
interventions. The advancement of effective immunotherapy relies on a compre-
hensive understanding of the complex interplay between tumors and the immune
system, encompassing both cellular communication and soluble signaling dynam-
ics that inuence immune evasion or tumor suppression. This chapter has detailed
the contributions of key immune cells and the mechanisms governing tumor–TME
interactions, highlighting their signicance for therapeutic design. Several emerging
strategies mentioned in this chapter will aid in mapping and understanding these
interaction networks with spatial and temporal precision, facilitating the develop-
ment of combination therapies that counteract immunosuppressive mechanisms
while enhancing cytotoxic immune activity.
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