Low SLC8A1 in Colorectal Cancer Dictates Radiotherapy Resistance Through Calcium‐Dependent ANXA2 + sEVs Driving M2 Polarization of TAMs

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ABSTRACT Background and Aims Tumors actively remodel the tumor microenvironment (TME) to foster therapy resistance. However, the underlying mechanisms remain poorly defined. This study aims to characterize how colorectal cancer (CRC) cells drive TME remodeling to promote radioresistance. Methods A radioresistant CRC cell line was established via serial in vivo irradiation. Single‐cell RNA sequencing characterized TME alterations. The role of tumor‐derived small extracellular vesicles (sEVs) in macrophage polarization was assessed. Proteomic analysis identified ANXA2 as a key sEVs cargo, and calcium‐dependent sEV secretion was investigated through SLC8A1 modulation. Clinical relevance analyses were further assessed. Results The radioresistant model exhibited enhanced treatment resistance to irradiation and increased infiltration of M2‐like tumor‐associated macrophages (TAMs), while TAM depletion restored radiosensitivity. Tumor‐derived sEVs promoted M2 polarization by activating STAT6 phosphorylation, with ANXA2 as the key functional cargo. Further analysis revealed that SLC8A1 deficiency increased intracellular Ca 2 + levels, boosting secretion of ANXA2 + sEVs and subsequent TAM M2 polarization. Clinically, low SLC8A1 expression correlated with higher M2 TAM infiltration, poorer therapeutic response, and worse survival outcomes in CRC patients. Conclusion CRC cells with low SLC8A1 expression remodel the TME to foster radioresistance via calcium‐dependent secretion of ANXA2 + sEVs and subsequent M2 polarization of TAMs.