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26 The Dynamics of Tumor Microenvironment and Therapeutic Targets
body’s immune defenses, is a dynamic process leading to immune tolerance and
therapeutic resistance. Blocking these immune evasion mechanisms is essential for
improving the efcacy of modern immunotherapies and conventional treatments and
for modifying the TIME to favor anticancer immunity.
Innate and adaptive immune cells found in the TIME include macrophages, neu-
trophils, natural killer (NK) cells, dendritic cells (DC), myeloid-derived suppres-
sor cells (MDSCs), T cells, and B cells. These cells can exhibit both antitumor and
protumor functions, depending on their phenotype and the signals they receive from
the surrounding environment (Turlej et al. 2025). The inuence of immune cells in
the TIME remodeling is multifaceted. They can alter the balance between immuno-
suppression and immune activation, modulate angiogenesis and lymph-angiogenesis,
affect tumor cell proliferation and metastasis, contribute to extracellular matrix
remodeling, and inuence the efcacy of cancer therapies. Understanding the com-
plex interactions between immune cells and other components of the TIME is crucial
for developing effective cancer treatments, including immunotherapies that aim to
harness the power of the immune system to combat cancers. T cells are one of the
key players in tumor immunity (Chen et al. 2023). Tumor-associated macrophages
(TAMs) can polarize into either M1 (antitumor) or M2 (protumor) phenotypes. M2
macrophages promote angiogenesis, tumor cell proliferation, and immunosuppres-
sion (Toledo et al. 2024). Dendritic cells present tumor antigens to T cells to initi-
ate immune responses, whereas natural killer (NK) cells eliminate tumor cells and
recruit other immune effectors (Marmonti, Oliva-Ramirez, and Haymaker 2022;
Portale and Di Mitri 2023). B cells contribute through tertiary lymphoid structures
(TLS), antigen presentation, cytokine production, and antibody generation (X. Wu
et al. 2025).
Over the past several decades, a wide range of therapeutic approaches target-
ing both innate and adaptive immune cells have been developed. These strategies
encompass combination treatments with immune checkpoint inhibitors (ICIs), den-
dritic cell vaccines, toll-like receptor (TLR) agonists, engineered cell therapies such
as CAR-T cells, CAR-macrophages (CAR-Ms), and CAR-natural killer cells (CAR-
NKs), as well as the use of CSF1R inhibitors, chemokine blockade, and cytokine-
based therapies (Hadiloo et al. 2023; Pan et al. 2022; L. Peng, Sferruzza et al. 2024).
Additional immune checkpoint blockade (ICB) has revolutionized cancer treatment,
its success is limited to a subset of patients. Tumors are often classied as “cold”
(immune-desert) phenotypes and “hot” (immune-inamed) phenotypes based on
their TIME prole and how they respond to immunotherapy. Additionally, there is
a more nuanced “excluded” immune phenotype, positioned between the “cold” and
“hot” categories, known as the immune “excluded” type. Hot tumors, rich in inltrat-
ing CD8+ T cells and pro-inammatory cytokines, respond well to ICB. Meanwhile,
the TIME of cold tumors are immunosuppressive and lacks immune cells that ght
cancer, eventually respond poorly to immunotherapy. Tumor cells undergo immu-
noediting to reduce immunogenicity, thereby preventing immune inltration. It is
widely accepted that ICB therapy exerts limited efcacy against these “cold” or
“altered” tumors, necessitating combinations with other therapeutic modalities to
enhance immune cell inltration into tumor tissue and convert “cold” or “altered”
27Shaping Cancer
tumors into “hot” ones. To overcome resistance in cold tumors, therapeutic strategies
aim to reprogram them into hot tumors. These include the use of immune checkpoint
inhibitors (ICIs) to disrupt inhibitory pathways, as well as approaches such as vas-
cular normalization (targeting endoglin/CD105) to improve immune cell access to
tumor sites (Ollauri-Ibanez, Ayuso-Inigo, and Pericacho 2021).
In this chapter, we explore the key hallmarks of malignant and immune cell inter-
actions that reshape the TIME leading to immune evasion, and therapy resistance.
We also highlight promising therapeutic strategies that aim to overcome these barri-
ers and improve clinical outcomes.
2.2 KEY IMMUNE PHENOMENA SHAPING THE TIME
Complex and dynamic environment of the TIME can be important for a tumor’s
prognosis and how it responds to targeted, chemo, radiation, and immunotherapy.
2.2.1 phagoCytosis
Phagocytosis plays a complex and multifaceted role in the tumor microenvironment
(TME), with both pro- and antitumor effects. Phagocytosis of tumor cells by tumor-
associated macrophages (TAMs) impacts innate immunity. This process allows for
the direct elimination of cancer cells by macrophages. Macrophages process cellu-
lar proteins derived from engulfed tumor cells and present those tumor antigens to
CD8 T cells, potentially stimulating a cytotoxic T cell response against the cancer
(Guan et al. 2025). Paradoxically, phagocytosis can also lead to immune suppres-
sion. The uptake of apoptotic cells (efferocytosis) by macrophages often promotes
anti-inammatory functions, potentially dampening the overall immune response
in the TME (Z. Liu, Li et al. 2025). Phagocytic TAMs show increased expression of
oxidative phosphorylation (OXPHOS) proteins, higher mitochondrial content, and
enhanced functional utilization of OXPHOS (Gonzalez et al. 2023). Phagocytosis
of neoplastic cells reprograms macrophage metabolism, predominantly increasing
OXPHOS and metabolic genes. This metabolic shift correlates with worse clini-
cal outcomes in human cancers. Phagocytosis is also responsible for the polariz-
ing M1/M2 TAMs balance within the TME. Enhanced phagocytosis by M1-TAMs
has the potential to directly control tumor progression by eliminating cancer cells
(Lecoultre, Dutoit, and Walker 2020). TME elements educate M1 antitumor TAMs
into by dampening their phagocytic activity against tumor cells (Prager and Watzl
2019). Phagocytosis of neoplastic cells can sustain immune-suppressive TAM pheno-
types, potentially promoting tumor progression. M2-TAMs promote distant metas-
tasis of tumor cells through a process called semi-phagocytosis. TAMs have been
shown to involve in metastatic invasion by serving as anchors for circulating tumor
cells, allowing their extravasation (Qian et al. 2009; Rodriguez-Tirado et al. 2022).
A deeper understanding of phagocytic mechanisms within the TME has the poten-
tial to inform the development of combination therapies aimed at modulating tumor-
associated macrophage (TAM) activity alongside conventional cancer treatments.
Beyond their established role in regulating T cell function and survival, the PD-1/
28 The Dynamics of Tumor Microenvironment and Therapeutic Targets
PD-L1 immune checkpoint pathway has also been shown to inuence macrophage
phagocytosis, promoting the clearance of tumor cells (Zhou, Liu, and Huang 2021).
One of the key regulators of phagocytosis in the TME is CD47, an anti-phagocytic
signal often overexpressed by tumor cells to evade immune-mediated destruction.
CD47 interacts with signal regulatory protein alpha (SIRPα) on macrophages, trans-
mitting a “don’t eat me” signal that suppresses phagocytic activity. Consequently,
therapeutic strategies targeting the CD47-SIRPα axis are being actively investigated
to enhance macrophage-mediated tumor clearance (Che et al. 2025).
In summary, phagocytosis within the TME serves as a double-edged sword,
capable of both inhibiting and promoting tumor progression. Its role extends beyond
direct tumor cell elimination to include reshaping the immune milieu, driving
metabolic alterations, and potentially inuencing metastatic behavior. Targeting
phagocytic pathways to amplify their antitumor effects while limiting immunosup-
pressive consequences represents a promising strategy in the advancement of cancer
immunotherapy.
2.2.2 aNtigeN preseNtatioN
Antigen presentation in the TME is a complex, dynamic process that plays a crucial
role in generating antitumor immune responses. While traditionally thought to be
primarily carried out by professional antigen-presenting cells (pAPCs), recent evi-
dence has revealed a more diverse landscape of antigen presentation within the TME.
Antigen presentation in the TME involves a complex interplay between pAPCs and
aAPCs, metabolic as well as growth factors, and specialized microenvironments.
Understanding these dynamics is crucial for developing effective immunotherapies
and enhancing antitumor immune responses.
Innate immune cells, particularly dendritic cells (DCs), act as pAPCs that bridge
the innate and adaptive immune systems (Wijfjes et al. 2023). DCs process and
present tumor antigens to T cells, activating them and initiating adaptive immune
responses. DCs can present antigens on both MHC class Iand II molecules, allow-
ing them to activate both CD8+ and CD4+ T cells (Del Prete et al. 2023). Unlikely
DCs, macrophages including granulocytes (eosinophils, neutrophils, and basophils)
need to get activated before turning professional phagocytes. Monocytes mature into
macrophages, matured and activated macrophages phagocytose foreign elements and
present them to T or B cells, eventually give rise to adaptive immunity. While they
have traditionally been considered less effective than DCs in antigen presentation,
recent studies have shown that certain TAMs in the TME inuence antigen presenta-
tion. TAM subsets, such as CD206+ macrophages, can cross-present tumor antigens
to CD8+ T cells (Modak et al. 2022). Macrophages can also elevate antigen presenta-
tion by taking up necrotic cells. Moreover, epithelial cells, vascular endothelial cells
(VECs), broblasts present in the TME, and cancer cells themselves are considered
“amateur” antigen-presenting cells (aAPCs) as they present tumor antigens on both
MHC class Iand II molecules (Darragh and Karam 2022). These aAPCs greatly
outnumber pAPCs in the TME and may play a signicant role in priming antitumor
immune responses.
29Shaping Cancer
Tertiary lymphoid structures (TLS) within tumors represent privileged sites for
local antigen presentation (X. Wu et al. 2025). Mature DCs enriched in immuno-
regulatory molecules (mregDCs) accumulate in these structures, facilitating the acti-
vation, proliferation, and differentiation of T cells in close proximity (Badillo et al.
2024; Reste et al. 2024). Several recent reports have demonstrated the importance
of B cells within the TME precisely within TLS. Apart from generating antibodies
and an antibody-mediated memory response against foreign agents, B cells are also
capable of functioning as pAPCs to activate antigen-specic CD4 and CD8 T cells.
Antigen presentation through B cells can be through antigen-specic (B cell recep-
tor [BCR] dependent) or antigen-nonspecic (BCR independent) mechanisms and
can be modulated by a variety of intrinsic and external factors (Rastogi et al. 2022).
Interestingly, the TME often impairs immune cell function through various
mechanisms such as, inhibiting of DC maturation and migration, alteration of anti-
gen captures abilities, downregulation of costimulatory molecules, and so on. These
impairments can signicantly reduce the effectiveness of DCs in generating robust
antitumor immunity. In addition to T-cell-based therapy, B cells are also increasingly
being evaluated as cellular therapies. The metabolic state of the TME signicantly
impacts antigen presentation. Cancer cells often reprogram their metabolism to sup-
port rapid proliferation, which can limit the availability of nutrients for immune
cells. This metabolic competition can impair the proper metabolic reprogramming
of APCs during recruitment, differentiation, activation, and antigen presentation.
2.2.3 CaNCer immuNoeditiNg
The cancer immunoediting hypothesis proposes that tumors can alter their surround-
ing immune landscape to dampen immune activity and avoid immune recognition.
One key mechanism involves reprogramming immune cells, shifting them from
cytotoxic effectors to immunosuppressive regulatory phenotypes. Cancer immu-
noediting links three phases of cellular and molecular events, such as elimination,
equilibrium, and escape, by which the dynamic immune system not only detects and
eliminates cancer cells but also inuences which tumor cells survive, thereby shap-
ing the overall ability of the tumor to be recognized by the immune system, precisely
immunogenicity (Amin et al. 2024; Gubin and Vesely 2022; Z. Zhang et al. 2024).
Overall process can inadvertently promote tumor growth and evolution by selecting
for treatment resistant malignant cell variants that are less susceptible to immune
attack (Alban et al. 2024; Amin et al. 2024). Immune cells such as tumor-associated
lymphocytes (TALs), myeloid-derived suppressor cells (MDSCs), tumor-associated mac-
rophages (TAMs), and double-negative (DN) T cells undergo immunoediting and
play critical roles in modulating the immune response (Jaume 2025). In addition,
cytokines, chemokines, and other signaling molecules facilitate communication and
regulation among immune cells within the tumor microenvironment.
Cancer immunoediting describes the dynamic interaction between the immune
system and tumor cells, encompassing three phases: elimination, equilibrium, and
escape. In the elimination phase, both innate and adaptive immune components tar-
get and destroy nascent tumor cells, a process aligned with the concept of “cancer
30 The Dynamics of Tumor Microenvironment and Therapeutic Targets
immunosurveillance.” Failure to eliminate all malignant cells leads to the equilib-
rium phase, where immune pressure selects for tumor variants with reduced immu-
nogenicity or acquired compensatory resistance mechanisms to maintain tumor
dormancy. Eventually, some tumor cells may adapt further, enabling them to evade
immune control and enter the escape phase, characterized by immune suppression
and unchecked tumor growth. Understanding these phases is critical for developing
effective immunotherapies (O’Donnell, Teng, and Smyth 2019).
The concept of cancer immunoediting, which evolved from and rened the earlier
theory of cancer immunosurveillance, provides a foundational framework for under-
standing both the historical limitations and the recent successes of cancer immu-
notherapy. Agents developed against programmed cell death—programmed cell
death ligand-1 (PD-1/PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-
4), and lymphocyte-associated gene 3 (LAG3)—are termed as checkpoint inhibi-
tors (ICIs) and aim to restore immune function, enhancing tumor elimination (Aden
et al. 2025; Schaub and Tang 2025; M. Wang et al. 2021). Various tumor-inltrating
lymphocytes (TILs) subsets are recognized as crucial effectors for the efcacy of
ICIs (He et al. 2025; Lopez de Rodas et al. 2025). However, resistance mechanisms
often overlap with those seen during immunoediting. Strategies that prevent immune
escape such as enhancing tumor antigen expression, may sustain immune surveil-
lance. Additionally, expression of “secreted immune checkpoint,” such as sLAG3,
sCD109, etc., are correlated with antitumor ability of T cells (Cui et al. 2025; Pitts,
Schlom, and Donahue 2024).
Neoantigens variants are one of major products of immunoediting that arise
from tumor-specic genetic (somatic) mutations, resulting in unique proteins on
the surface of cancer cells that are absent in normal tissues. Mapping these highly
immunogenic neoantigens to clonal dynamics, evolutionary trajectories, and clini-
cal responses reveals strong selective pressure against clones harboring immuno-
genic neoantigens (Alban et al. 2024). Notably, the early loss of oncogenic drivers,
somatic mutations, and neoantigens during therapy correlates with improved clinical
outcomes. Furthermore, immunoediting and the emergence of neoantigen variants
signicantly inuence the efcacy of immune checkpoint blockade. Both CAR-T
and CAR-NK cell therapies have demonstrated consistent and encouraging efcacy
in cancers (L. Peng, Sferruzza et al. 2024). Adoptive T cell therapy using chimeric
antigen receptor T cells (CAR-T) represents another promising approach in cancer
immunotherapy, wherein a patient’s T cells are genetically modied to specically
recognize and eliminate cancer cells. CAR-T cells are engineered to incorporate
an scFv domain for antigen recognition, co-stimulatory domains such as CD28 or
4–1BB, and an activation domain (CD3ζ) to enhance T cell cytotoxicity (S. Zheng,
Asnani, and Thomas-Tikhonenko 2019). However, tumor cells can evade CAR-T-
mediated killing by leveraging immunoediting mechanisms, including antigen loss,
downregulation of target antigens, or trogocytosis—the transfer of tumor antigens to
CAR-T cells—thereby reducing antigen density on the tumor surface (Mitra et al.
2023). Although CAR-NK cells offer logistical advantages as “off-the-shelf” thera-
peutics—eliminating the need for personalized manufacturing and enabling greater
accessibility compared to patient-specic CAR-T cells—they remain susceptible to
immune evasion through antigen loss or downregulation driven by immunoediting.
31Shaping Cancer
Therefore, the ability of cancer cells to adapt through immunoediting poses signi-
cant obstacles to therapies such as CAR-NK/T cell treatment, particularly in certain
clinical contexts (Ikeda 2025). Afew comprehensive computational methods for can-
cer immunoediting were developed to systematically evaluate and quantify immu-
noediting to benet ICIs (Aran, Sirota, and Butte 2015; T. Wu et al. 2022).
In essence, cancer immunoediting describes the complex interplay between the
immune system and cancer cells, thereby shapes the evolution and progression of
tumors through a process of selection and adaptation within the TME. The challenges
posed by immune editing have provided a new perspective of immune checkpoints,
have highlighted the limitations of single-agent therapies and prompted exploration
of combination strategies. Consequently, current research is increasingly focused
on improving the efcacy of ICI-monotherapy through combinatorial approaches
and the identication of novel neoantigens as immunotherapy targets. With in-depth
knowledge about intricate mechanisms of cancer immunoediting, researchers can
develop more personalized and effective cancer immunotherapies that can ultimately
lead to better patient outcomes.
2.2.4 CytokiNe-ChemokiNe-ComplemeNt mediated Networks iN the time
The TIME plays a crucial role in driving both primary and acquired resistance to
treatment. During tumorigenesis, TIME shifts immune responses from antitumor to
protumor activities, contributing to the failure of therapies ranging from chemother-
apy and radiation to immunotherapy (D. Liu, Liu et al. 2025). Secretome of immune
cells is the collection of cytokines and chemokines that play pivotal role in shaping
up the TME that aid in cell-to-cell communication and regulate some vital biological
processes such as tumor survival and development (P. Liu and Sun 2025; Nengroo,
Verma, and Datta 2022; J. Yang, Lu, and Li 2025). While cytokines orchestrate inter-
actions between tumor-immune/stromal cells, but chemokines provide migratory
guidance cues to these cells. Spatial distribution of immune cells in TIME is diverse
and chemokines inuences recruitment and positioning of all polarized subtypes of
T cells, B cells, monocytes/macrophages, and so on.
Pro-inammatory cytokines play a key role in promoting cancers by activating
oncogenic pathways like MET, PI3K/AKT, STAT-3, NF-κB, and so on. These mole-
cules also attract stromal cells, which help shape a tumor-promoting TME. Conversely,
anti-inammatory cytokines like IL-10 and TGF-β dampen the activity of cytotoxic
T cells and encourage the development of immune-regulatory cells, such as Tregs
and neutrophils, which facilitate immune escape. The polarization states of immune
cells within the TME are more intricate than the simple classication into pro- or
anti-inammatory roles, largely due to the diverse expression patterns of cytokines
and chemokines (Bhat et al. 2022). Furthermore, innate immune cells release a wide
array of these signaling molecules, shaping the recruitment, activation, and behavior
of adaptive immune cells. For instance, M1-polarized macrophages generate pro-
inammatory cytokines that enhance antitumor, cytotoxic T cell activity, whereas
M2-polarized macrophages produce immunosuppressive molecules that can dampen
T cell responses and support tumor growth (Avila-Ponce de Leon et al. 2023). The
interplay between inammatory and anti-inammatory signals is essential for tumor
32 The Dynamics of Tumor Microenvironment and Therapeutic Targets
development and impacts therapies responses, including efcacy of immune check-
point inhibitors (H. Wang et al. 2024). Disruption of cytokine regulation can lead
to persistent inammation, which in turn contributes to genetic mutations, epigen-
etic alterations, and resistance to treatments. Key pro-inammatory cytokines, such
as IL-1, IL-6, IL-8, TNF-α, IFN-γ, and GM-CSF, affect numerous cellular func-
tions. These include promoting tumor growth, DNA damage, blood vessel formation
(angiogenesis), epithelial-mesenchymal transition (EMT), increased PD-L1 expres-
sion, support metastasis, and immune evasion (Landskron et al. 2014; H. M. Lee,
Lee, and Chang 2022). They also aid in the recruitment of immune cells like myeloid
cells and neutrophils within tumor vicinity. These cytokines are released by various
immune and tumor cells, including macrophages, dendritic cells, T cells, NK cells,
and tumor cells themselves. On the other hand, key anti-inammatory cytokines,
such as IL-10, TGF-β, and IL-37, are produced within the TME by cells like regula-
tory T cells, B cells, NK cells, monocytes, and macrophages (Gu et al. 2023; Yi et al.
2024). These molecules help reduce the production of pro-inammatory cytokines,
inhibit immune cell activation, prevent dendritic cell maturation, and suppress Th1
responses. Altogether, this promotes immune tolerance and enables tumor progres-
sion by allowing cancer cells to evade the immune system.
Beyond cytokines, a comprehensive understanding of chemokine signaling mech-
anisms and the receptor-mediated pathways they activate holds signicant clinical
relevance. Deciphering the functional architecture of the TIME necessitates insight
into the diverse and complex roles chemokines play (Mempel, Lill, and Altenburger
2024; Saxena and Singh 2021). As primary mediators of leukocyte trafcking,
chemokines facilitate the inltration of protumor inammatory myeloid cells and
immunosuppressive populations into both primary tumors and metastatic sites.
Additionally, they drive various pro-oncogenic processes reliant on cellular motility,
including angiogenesis through endothelial cell migration, recruitment of mesenchy-
mal stem cells (MSCs), and organ-specic metastasis (Morein, Erlichman, and Ben-
Baruch 2020). Among the chemokines, CXCL12 has emerged as a central regulator
of tumor progression, primarily through its interactions with canonical receptors
CXCR4 and CXCR7 (also known as RDC1) (Cambier, Gouwy, and Proost 2023; Y.
Yang et al. 2023). Other key chemokines such as CXCL8 (IL-8), CCL2 (MCP-1),
and CCL5 (RANTES), along with their corresponding receptors, also contribute to
cancer progression and metastatic dissemination (Han et al. 2021; M. Xu et al. 2021;
Yosh imur a et al. 2023). Moreover, non-traditional chemokine signaling axes includ-
ing CXCR7 and atypical chemokine receptors (ACKRs), particularly ACKR3, play
critical roles in modulating the spatial organization of tumors and the surrounding
microenvironment (R. Lee et al. 2024; Samus and Rot 2024).
The complement system is a group of proteins that interact sequentially to amplify
immune functions, helping antibodies and phagocytes more effectively remove for-
eign particles including tumors and cellular debris. It is another vital component of
innate immunity and has traditionally been considered an antitumor effector mecha-
nism. However, in the TME, complement-mediated immune responses have been
shown to promote chronic inammation, activate cancer-related signaling pathways,
and inhibit antitumor immune responses. Above all, a complement system exhibits a
complex, paradoxical role within the TIME (Ain et al. 2021). The crosstalk among
33Shaping Cancer
the complement system (e.g., C1q) and cancer cells (complement receptors) and other
immune cells (T cells) in the TME aid in reprogramming functions of tumor cells in
favor of either progression (C5a/C5aR1 axis) or suppression (C1q/gC1qR and cC1qR
axis) (Ain et al. 2021). C3a and C5a recruit MDSCs to suppress antitumor immune
responses (Senent et al. 2022). Altogether, the complement system regulates angio-
genesis, tumor-stromal composition, and spatial distribution across the tissues, often
metastasis.
2.3 INNATE IMMUNE NETWORKS IN THE TIME
Recent advances in cancer therapy have focused on harnessing the power of innate
immune pathways to enhance antitumor immune responses and potentially eradicate
“cold” tumors. Innate immunity plays a crucial role in cancer immunotherapy, serv-
ing as a critical component in detecting, capturing, and processing cancer antigens to
trigger adaptive immune responses (Rameshbabu et al. 2021).
Activation of innate immune pathways can profoundly alter the TME, and target-
ing key innate immune cell types, such as macrophages, natural killer (NK) cells,
and dendritic cells (DCs), has shown potential in enhancing antitumor immunity
(Y. Zhang et al. 2023). Stimulation of several innate immune component, such as
pattern recognition receptors (PRRs)—including toll-like receptors (TLRs), NOD-
like receptors (NLRs), RIG-I-like receptors (RLRs), and cGAS/STING pathway—
has emerged as a promising strategy (Hu et al. 2024; Rameshbabu et al. 2021).
Furthermore, the innate immune-cell-derived complements, chemokine and cyto-
kine systems, play pivotal regulatory roles in tumor–TME crosstalk (Artero et al.
2025). Despite the promising potential of innate immunity-based cancer therapies,
the role of innate immune pathways varies depending on tumor development stage,
pathway status, and specic cell types (Hu et al. 2024). Therefore, bridging the gap
between preclinical success and clinical application remains a signicant challenge
for implementation of innate immunity modulatory treatment. Activation of innate
immune pathways can paradoxically promote tumor progression in some cases (Cao
and Kagan 2023; C. Li, Yu et al. 2024).
According to many studies, DCs play a vital role in helping initiate the antitumor
immunity, so it further insists on increasing the interest in improving the status and
numbers of DCs to suppress the progression of tumor. Within the TME, DCs can
take up antigens continuously, and can sense the danger signals with the help of pat-
tern recognition receptors (PRRs) and thereby recognizes damage-related molecular
patterns (DAMPs) from malignant cells. These signals help enable the DCs to initiate
tolerance and help in the immunogenicity properties in an arranged, subset-specic
manner (Joffre et al. 2009). Therefore, it helps in better understanding about the
roles of DCs in the TME, so further studies are required for understanding the func-
tion of the subsets of DC. DCs are derived from the common myeloid progenitor
cells (CMPs). Under the inuence of the inammatory conditions, the CMPs dif-
ferentiate into monocytic dendritic cells (moDCs) with the help of the expression of
the transcription factor Nur77 (Collin and Bigley 2018). CMPs differentiate into the
common dendritic cell progenitors (CDPs) in the absence of Nur77, which results in
conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs). cDCs
34 The Dynamics of Tumor Microenvironment and Therapeutic Targets
can further be subdivided into two sets, type I(cDC1) and type II (cDC2) (Collin and
Bigley 2018). cDC1 perform cross-presentation of antigens to MHC class Iand start
type Icytotoxic immune responses. cDC2 activates innate lymphoid cells 2 (ILC2)
and T
H
2 cells and induces ILC3 and T
H
17 immune responses. In pDCs, all the four—
CD123, CD303, CD304, and CD45RA—are expressed. The cDC1 expresses CD141,
DEC205, Clec9A, and XCR1, and cDC2 expresses CD1c, CD1a, and CD103 (Wylie
et al. 2019). VEGF inhibitors has been applied to enhance the maturation of DC in
patients (Nefedova et al. 2004; Yu, Pardoll, and Jove 2009). Tyrosine kinase 3 ligand
(FLT3-L) dependent expansion and activation of cDCs recruit antitumor and tumor-
protecting lymphocytes. Therefore, suppression of tumors can be achieved in vivo by
systemic injection of FLT3-L (Regnier et al. 2023). DC vaccine provides a promising
method of immunotherapy, along which relevant clinical trials are ongoing further.
DC vaccines, e.g., DCVax-L, is another therapeutic option against cancers and has
shown to prolong overall survival among the glioblastoma patients in a phase III
clinical trial (van Willigen et al. 2018). Neoantigen-DC vaccines encompassing anti-
CD38 and CpG aid in elevating the tumor immunity against the ICI-therapy-resistant
mouse lung cancer cell lines (Wylie et al. 2019).
Macrophages play key role during carcinogenesis. Human peripheral blood mono-
cytes (non-classical CD14lo CD16hi and classical CD14hi CD16lo) differentiate into
tumor-associated macrophages (TAMs) by stromal- and tumor-cell-derived growth
factors and the chemokines in the TME, and express a variety of immune checkpoints
that impact immune functions. TAMs or M2 polarized macrophages are predomi-
nant tumor-inltrating immune cells in the TME and promote the development of
tumor. High density of TAMs in TIME are often associated with the poor progno-
sis and decreased overall survival. TAMs enhance tumor progression and epithelial-
mesenchymal transition (EMT) in several ways, including stimulating angiogenesis
and lymph-angiogenesis (Bingle, Brown, and Lewis 2002). Therefore, perturbing
TAM activity and induce phenotypic twitch to antitumor M1 type has clinical benets.
Macrophage-based immunotherapy includes the following: immune checkpoint inhibi-
tors, monoclonal antibodies, cell adoptive therapy, and small molecule inhibitors. Such
therapies directly reduce the number of macrophages and prevent the recruitment of
TAMs, enhancing the ability of phagocytic killing or targeting the surface molecule
of TAMs. Certain drugs, such as emactuzumab and IMC-CS4, inhibit tumor devel-
opment by deducting the number of macrophages (Dowlati et al. 2021; Gomez-Roca
et al. 2022). Additionally, it is found that the immune checkpoint inhibitors enhanced
the phagocytosis of TAM. Other inhibitors such as CD47 inhibitor (Hu5F9-G4), CD40
antibody (selicrelumab), and trastuzumab reduce tumor burden via TAMs (Advani
et al. 2018; Shi et al. 2015). Targeting indoleamine 2, 3-dioxygenase (IDO) molecule
on the macrophage surface has been benecial in human trials (Adams et al. 2015).
In addition to these, adoptive therapy based on macrophages, can also inhibit
tumor progression as well. Single infusion of a human CAR-macrophage helps in
reducing the burden of tumor, thereby increasing the overall survival in two solid
tumor affected xenograft mouse models and more efcient than M1 macrophages
(Klichinsky et al. 2020). Nanoparticle-based drugs reprogram TAMs and benets
cancer immunotherapy (Kandasamy, Karuppasamy, and Krishnan 2023; Lu et al.
2024; X. Peng, Fang et al. 2024).
35Shaping Cancer
NK cells originate from the pluripotent hematopoietic cells but found to be pres-
ent in both blood and in various lymphoid organs. They play a vital role in provid-
ing defense against viruses and tumors. NK are subdivided into two major subsets:
immature NK cells (CD56
bright
CD16
dim
) and mature (CD56
dim
CD16
bright
) types
(Bjorkstrom, Ljunggren, and Michaelsson 2016). NK cells express either activating
receptors (NKRs) or inhibitory receptors (KIRs) and controlled by tumors as they
exclusively express ligands for NK cell activation receptors (Handgretinger, Lang,
and Andre 2016; Smyth et al. 2005). Once activated, NK cells kill tumor cells in the
TME. NK cells affect tumors either by directly killing (natural cytotoxicity) or by
antibody dependent cell cytotoxicity (ADCC: receptor of the NK cells binds to the Fc
portion of the IgG antibodies) pathway. NK-cell-mediated ADCC enhance efcacy
of monoclonal antibody-based immunotherapy (Kaur et al. 2021). Furthermore, NK
cells enhance potential of adoptive cell therapy platform (Maia et al. 2024).
Interestingly, NK cells offer signicant advantages over T cells, including major
histocompatibility complex class I(MHC-I) independent tumor recognition and low
risk of toxicity, even in an allogeneic setting. Further improvements in NK cell func-
tion can be reached by inducing memory-like NK cells, developing chimeric antigen
receptor (CAR) NK cells, or isolating NK-cell-based tumor-inltrating lymphocytes
(TILs). The activated NK cells also release the cytotoxic granules (granzymes, per-
forins) or by inducing the death-receptor-mediated apoptosis (Fas/Fas ligand) or the
TNF-related apoptosis-inducing ligand, P13K pathway associated with the killing
and thereby can help killing the tumor cells (Cluff et al. 2022; T. Li et al. 2019;
Prager and Watzl 2019). Additionally other than killing of the tumor cells, NK cells
also secrete chemokines and cytokines to play an immunomodulatory function as
well. Along with that, NK cells can also produce C-C motif ligands, which include
the CCL3, CCL4, CCL5, X-C motif chemokine ligand 1 (XCL1) and C-X-C-motif
chemokine ligand 8 (CXCL8), which attract a variety of immune cells to transfer
the tissue and inhibit the progression of tumor (Gotthardt and Sexl 2016). In addi-
tion to this tumor-killing role, there are certain subtypes of NK cells, e.g., CD39;
overexpressing populations are related with the poor progenesis, which may help in
the development of tumors (such as lymphoma, breast cancer, and gastric cancer)
(Duault et al. 2021; Y. Zheng et al. 2020). IL-2, IL-15, IL-18, and IL-21 cytokine
supplementation can help improve the activity of NK cells and thereby enhance their
tumor-killing abilities (Conlon et al. 2015; Conlon et al. 2019). CTLA4 blockage
prevents the dysfunction of NK cells and thereby slows the tumor growth, which
improves the overall survival of patients (Sottile et al. 2019). Tumors have been seen
to upregulate the ligands of the NK-cell-activating receptors (NKG2D) and the nat-
ural cytotoxic receptors (NCRs), thus inducing NK-cell-mediated cytotoxicity and
tumor cell apoptosis (Khatua et al. 2020). CAR-NK, which gets modied genetically
by the chimeric antigen receptors (CARs) on the immune cells, directly targets the
tumor-specic antigens and has resulted in the promising results in preclinical stud-
ies related to ovarian, breast, prostate, and colon cancers (Dehghan et al. 2024; W.
Li, Wang et al. 2024).
MDSCs, a regulatory cell population, originate from the myeloid progenitor
cells. Diverse soluble factors aid in mobilizing MDSCs into the TME and deter-
mine the diversity in their phenotypes. MDSCs are subdivided into three groups: