Kidney renal clear cell carcinoma-derived migrasomes mediate immunosuppressive microenvironment by inducing M2 macrophage polarization.

Kidney renal clear cell carcinoma (KIRC) is characterized by a highly immunosuppressive tumor microenvironment (TME) that drives disease progression and limits therapeutic efficacy. Migrasomes, a recently identified class of extracellular vesicles, mediate intercellular communication; however, their specific role in KIRC immunity remains largely unexplored. Here, we show that TSPAN4, a key migrasome marker, is significantly upregulated in KIRC. KIRC-derived migrasomes effectively induce macrophage polarization toward the M2 phenotype, as evidenced by increased M2 marker expression and reduced M1 marker expression. In vitro, macrophages educated by KIRC-derived migrasomes significantly enhance tumor cell proliferation, migration, and invasion. Notably, TSPAN4 knockdown markedly attenuates this migrasome-induced M2 polarization. Collectively, our findings reveal that KIRC-derived migrasomes promote an immunosuppressive TME by driving M2 macrophage polarization, thereby facilitating tumor progression. This study provides mechanistic insights into immune evasion in KIRC and identifies migrasome-mediated communication as a potential immunotherapeutic target.