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Page 4 of 28 Cheng et al. Cancer Drug Resist. 2025;8:46

Hypoxia plays a critical role in macrophage recruitment and polarization toward the M2 phenotype. Hypoxia
stimulates the production of multiple migratory factors, including vascular endothelial growth factor
(VEGF), C-C motif chemokine ligand 2 (CCL2), CCL5, and CSF-1, by carcinoma and stromal cells . These
[41]
factors recruit and retain macrophages within hypoxic tumor regions . Once recruited, macrophages are
[42]
reprogrammed into an M2-like, tumor-promoting phenotype through cytokines secreted by hypoxic
cells [43,44] . As the tumor progresses, increasing hypoxic stress reduces the release of proinflammatory
cytokines such as IL-1β, TNF-α, and CCL17 by M1-skewed macrophages, thereby further promoting M2
polarization .
[45]

Hypoxic tumor cells primarily rely on anaerobic glycolysis for energy, resulting in excessive lactic acid
accumulation . Integrating with macrophage colony-stimulating factor, metabolic byproducts of glycolysis
[46]
inhibit the nuclear factor-κB (NF-κB) pathway, suppress nitric oxide (NO) and inflammation-related
cytokines, and upregulate VEGF, arginase-1 (Arg-1), and other M2-associated genes [47-49] . Under hypoxic
conditions, lactic acid strongly promotes M2-like polarization via HIF-1, Hedgehog, mammalian target of
rapamycin (mTOR), and monocarboxylate transporter/HIF-1α signaling pathways [50,51] . Additionally, G
protein-coupled receptors, which sense the acidic TME, induce inducible cAMP early repressor expression
by inhibiting NF-κB signaling, further enhancing M2-like polarization of TAMs [52,53] . Lactate also induces
histone lysine lactylation, a recently identified epigenetic modification, which upregulates M2-associated
gene expression, including ARG1 . Moreover, succinate released by tumor cells activates succinate receptor
[54]
1, driving TAM education toward the M2 phenotype through the succinate receptor 1-PI3K/HIF-1α
pathway [55] . Hypoxia-induced CXC motif chemokine ligand 12/CXC motif chemokine receptor 4
(CXCL12/CXCR4) signaling and the endoplasmic reticulum (ER) stress-associated IRE1-XBP1 pathway also
promote M2-like polarization [56,57] . Among these diverse pathways, Toll-like receptor, CXCL12/CXCR4, and
IRE1-XBP1 signaling are considered promising therapeutic targets, and inhibitors such as resiquimod,
BPRCX807, and KIRA6 have been reported [56-58] .

Overall, tumor hypoxia plays a pivotal role in reprogramming macrophages toward the M2 phenotype, and
TAMs in hypoxic tumors predominantly exhibit an M2-like rather than M1 phenotype .
[59]
The role of TAMs in resistance to immunotherapy
TAMs orchestrate multiple aspects of tumor progression [60,61] , and recent studies have highlighted their
complex roles in promoting immune evasion and resistance to immunotherapy. TAMs release various
immunosuppressive cytokines, primarily IL-10 and transforming growth factor-β (TGF-β). IL-10 inhibits
Th1 cell function and reduces the production of IFN-γ, IL-2, and TNF-α, thereby suppressing T cell immune
responses [62,63] . In addition, IL-10 promotes the activation of regulatory T cells (Tregs), further exacerbating
immunosuppression [64-66] . TGF-β suppresses T cell and natural killer (NK) cell generation and cytotoxicity,
while simultaneously enhancing the differentiation and activation of Tregs . TAMs also release chemokines
[67]
such as CCL2, which recruit immunosuppressive cells including myeloid-derived suppressor cells (MDSCs)
and Tregs into the TME, thereby intensifying immunosuppression . Arg-1 secreted by TAMs depletes
[60]
L-arginine, an essential metabolite for T cell function, leading to reduced T cell proliferation and impaired
activity . Indoleamine 2,3-Dioxygenase (IDO), which is upregulated in TAMs, contributes to tumor
[68]
immunosuppression by degrading tryptophan and generating immunosuppressive metabolites (e.g.,
kynurenine and hydroxytryptophan). These metabolites inhibit T cell function while promoting Treg
proliferation and activation . Moreover, TAMs secrete cytokines such as IL-6 and CCL20 to further recruit
[69]
Tregs [70,71] .

TAMs also play a key role in T cell exhaustion and functional inhibition. Persistent antigen-specific synaptic
interactions between TAMs and CD8 T cells prevent effective T cell activation and drive T cell exhaustion.
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