Myeloid cells shape tumor microenvironments and influence cancer progression

Recent advances in cancer research have underscored the critical role of myeloid cells in shaping tumor microenvironments (TME), influencing tumor progression, immune evasion, and therapeutic resistance. Myeloid cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), exhibit functional plasticity driven by interactions with tumor cells, stromal components, and metabolic adaptations. These cells not only directly promote tumor growth by enhancing angiogenesis, matrix remodeling, and metastasis but also suppress anti-tumor immunity through nutrient deprivation, oxidative stress, and cytokine-mediated inhibition of T and NK cells. Their dual roles—both pro-tumorigenic and occasionally anti-tumorigenic—highlight their complexity and context-dependent behavior across cancer types.

Metabolic reprogramming emerges as a central mechanism governing myeloid cell functionality. TAMs and MDSCs adapt to the nutrient-poor, hypoxic TME by upregulating glycolysis, fatty acid oxidation (FAO), and amino acid metabolism. For instance, glycolysis in TAMs supports immunosuppressive phenotypes via lactate production, which stabilizes HIF-1α and induces histone lactylation, promoting IL-10 and Arg1 expression. Similarly, lipid metabolism drives the accumulation of lipid-laden macrophages, which secrete chemokines like CCL20 to recruit regulatory T cells (Tregs), fostering immune tolerance. MDSCs rely on glutamine and fatty acid metabolism to sustain their survival and suppressive functions, often depleting arginine and tryptophan to impair T cell responses. These metabolic shifts are tightly regulated by tumor-derived signals, such as cytokines and extracellular vesicles, creating a feed-forward loop that perpetuates immunosuppression.

Chemotaxis, proliferation, and survival mechanisms further amplify myeloid cell infiltration within tumors. Tumor-secreted chemokines like CCL2, CXCL8, and CSF-1 recruit monocytes and MDSCs, while hypoxia and metabolic stress enhance their survival through pathways involving STAT3, NF-κB, and autophagy. Non-canonical sources, such as splenic hematopoietic stem and progenitor cells (HSPCs), contribute to myeloid cell accumulation, driven by tumor-induced emergency myelopoiesis. This extramedullary hematopoiesis, particularly in the spleen, generates myeloid-biased progenitors that migrate to tumors, replenishing immunosuppressive populations. Such mechanisms underscore the systemic nature of tumor-driven immune modulation.

Current therapeutic strategies targeting myeloid cells focus on disrupting their recruitment, survival, or metabolic activity. Clinical trials explore inhibitors of CSF-1R, CCR2, and CXCR2 to block chemotaxis, while metabolic interventions aim to inhibit glycolysis (e.g., PFKFB3 inhibitors), FAO (e.g., CPT1A blockers), or amino acid pathways (e.g., arginase and IDO inhibitors). Combining these approaches with immune checkpoint blockade (ICB) has shown promise in preclinical models, though clinical outcomes remain mixed due to compensatory mechanisms like PMN-MDSC infiltration or Treg expansion. Challenges persist in selectively targeting pro-tumor myeloid subsets without compromising anti-tumor immunity, necessitating deeper insights into subset-specific markers and functions.

Emerging single-cell technologies and spatial profiling reveal unprecedented heterogeneity among myeloid populations. Subsets like TREM2+ TAMs or PD-L1+ macrophages exhibit divergent roles depending on tissue context, metabolic state, and interactions with neighboring cells. For example, PD-L1+ macrophages in hepatocellular carcinoma correlate with favorable prognoses, contrasting their typically immunosuppressive role. Similarly, lipid-associated macrophages in triple-negative breast cancer drive resistance to ICB, emphasizing the need for precision targeting. Integrating multi-omics data with functional studies will refine classification systems and identify actionable vulnerabilities.

Future directions emphasize the importance of understanding dynamic interactions between myeloid cells and other TME components, including fibroblasts, neutrophils, and B cells. The concept of "onco-spheres" framing tumors as ecosystems highlights the interplay between local and systemic immunity. Therapeutic innovation may lie in modulating cholesterol metabolism, epigenetic regulators, or training innate immunity through β-glucan-like agents. Additionally, repurposing existing drugs—such as statins or glutamine antagonists—to disrupt myeloid cell function offers translational potential. Ultimately, overcoming therapeutic resistance requires a holistic approach that rebalances myeloid responses, enhances T cell efficacy, and disrupts tumor-immune crosstalk at both metabolic and transcriptional levels.