Molecular and metabolic reprogramming of tumor-associated macrophages in cancer immunotherapy

Tumor-associated macrophages (TAMs) are among the most abundant and functionally adaptable immune cells in many solid tumors. Rather than existing as fixed M1/M2 states, TAMs occupy dynamic phenotypic continua shaped by tumor-derived signals, stromal interactions, hypoxia, nutrient availability, and treatment pressure. Their molecular and metabolic programs can promote immune suppression, angiogenesis, invasion, metastasis, and resistance to immune checkpoint blockade, yet selected macrophage states can also support antigen presentation and antitumor immunity. Advances in single-cell and spatial multi-omics, lineage tracing, metabolomics, and functional perturbation have revealed substantial inter- and intratumoral heterogeneity. These findings create an opportunity to define actionable regulatory mechanisms and develop strategies that selectively deplete, reprogram, or therapeutically exploit specific TAM populations in combination with cancer immunotherapy.The goal of this Research Topic is to integrate mechanistic and translational studies that explain how molecular signaling and metabolic adaptation determine TAM identity, plasticity, and therapeutic function. A major challenge is moving beyond simplified polarization markers toward context-specific macrophage states with validated causal roles and clinically meaningful biomarkers. We aim to highlight advances in transcriptional and epigenetic regulation, post-transcriptional control, protein modification, lipid and amino-acid metabolism, mitochondrial function, ferroptosis and other cell-death pathways, as well as reciprocal signaling among tumor cells, macrophages, and lymphocytes. Particular emphasis will be placed on work that connects mechanistic discoveries to therapeutic intervention, including macrophage reprogramming, blockade of recruitment or survival pathways, metabolic targeting, engineered cellular or nanoparticle approaches, and rational combinations with immune checkpoint inhibitors, vaccines, radiotherapy, chemotherapy, or antibody-drug conjugates. Studies incorporating patient samples, spatial profiling, clinically relevant models, and treatment-response analyses are especially encouraged.This Research Topic welcomes Original Research, Reviews, Systematic Reviews, Methods, Brief Research Reports, and Perspectives addressing:• Molecular, transcriptional, epigenetic, post-transcriptional, and post-translational control of TAM phenotypes;• Metabolic reprogramming involving glucose, lipids, amino acids, mitochondria, redox balance, iron metabolism, and regulated cell death;• TAM heterogeneity, ontogeny, spatial organization, and plasticity across tumor types and treatment stages;• Crosstalk among TAMs, cancer cells, lymphocytes, stromal cells, and the microbiome in immune evasion, metastasis, and therapy resistance;• Biomarkers, imaging, single-cell or spatial multi-omics, and functional models for patient stratification and response monitoring;• Therapeutic strategies targeting macrophage recruitment, survival, checkpoints, phagocytosis, metabolism, or functional state, including combinations with immunotherapy and other anticancer modalities.Submissions should provide mechanistic depth or clear translational relevance. Descriptive studies without functional validation should explicitly define their biological or clinical significance. Please note that manuscripts primarily comprising computational analysis of public datasets must include appropriate experimental or clinical validation to be considered for peer review. Topic editors: Bisheng Cheng, Yaron Carmi Source: https://www.frontiersin.org/research-topics/84266/molecular-and-metabolic-reprogramming-of-tumor-associated-macrophages-in-cancer-immunotherapy