Mechanisms of SPP1+/TREM2+ Tumor- Associated Macrophag+s in Immunotherapy Resistance and Combined Targeted Therapy Strategies

Immunotherapy resistance in solid tumors is closely related to multi-level immunosuppression in the tumor microenvironment (TME), with tumor-associated macrophages (TAMs) playing a central role. This review summarizes the heterogeneity of TAMs and their interactions with cancer-associated fibroblasts (CAFs) and lactate metabolism, focusing on the mechanisms by which SPP1⁺ and TREM2⁺ TAMs mediate immunosuppression, matrix remodeling, and metabolic adaptation. SPP1⁺ TAMs can promote CD8⁺ T cell exhaustion and form a positive feedback loop with CAFs, while TREM2⁺ TAMs enhance immunosuppression through pathways such as PI3K/Akt/mTOR and NF-κB/STAT1. The CXCL9⁺/SPP1⁺ TAM ratio may serve as a potential biomarker for predicting immunotherapy response. Existing research indicates that targeting TAMs alone has limited efficacy, and combining them with immune checkpoint inhibitors and matrix and metabolic modulators may be more effective. Future research should strengthen biomarker-driven patient stratification and explore combined strategies such as lactate metabolism and epigenetic regulation to improve the response of "cold" tumors to immunotherapy.