Macrophage Trogocytosis of Tumor Cells Drives the Immunosuppression of Tumor Microenvironment

ABSTRACT Despite considerable advances in cancer immunotherapy, the persistent immunosuppressive tumor microenvironment (TME) seriously limits its performance in solid tumors. Here, we reveal that trogocytosis—an intercellular membrane transfer process—between tumor‐associated macrophages (TAMs) and cancer cells serves as a critical mechanism driving this immunosuppression. We demonstrate that trogocytosis efficiency, inversely correlated with tumor cell cortical stiffness, varies substantially across cancer types and dictates immunosuppressive intensity through upregulation of CXCL5 and Arg‐1, leading to CD8 + T cell exhaustion. Importantly, this mechano‐immunological axis is conserved in humans, as evidenced by study with human cell lines and a strong correlation between trogocytosis markers and T cell exhaustion in clinical patient samples. Increasing tumor cell stiffness with simvastatin effectively suppressed trogocytosis, reversed T cell dysfunction, and synergistically enhanced the efficacy of adoptive T cell therapy. These findings establish macrophage trogocytosis as a fundamental driver of immunosuppressive heterogeneity and highlight its targeting as a promising strategy to potentiate cancer immunotherapy.