Oncoprotein SND1-enriched exosomes facilitate melanoma lung metastasis by regulating CD47-SIRPα-mediated macrophage reprogramming.

Staphylococcal nuclease and Tudor domain containing 1 (SND1) is an emerging oncoprotein highly expressed in various tumors. Database analyses indicate that SND1 is enriched in tumor-derived exosomes, suggesting its potential role in modulating the tumor microenvironment (TME) via exosomes. Here, we demonstrated that SND1 served as a novel tumor-derived exosome (TEX) marker, influencing macrophage polarization by enriching exosomal membrane proteins. In mice, SND1 enriched in melanoma-derived exosomes promoted lung metastasis, accompanied by increased tumor-associated macrophage (TAM) infiltration. Conversely, SND1-deficient exosomes (ExoSND1-KO) shifted macrophage polarization toward an M1 phenotype, creating an anti-tumor immune microenvironment and inhibiting melanoma lung metastasis. Mechanistically, SND1 promoted ESCRT-dependent CD47 sorting, thereby facilitating its incorporation into melanoma-derived exosomes and allowing them to evade macrophage-mediated phagocytosis through the CD47-SIRPα axis. Consequently, macrophages failed to engulf TEXs or tumor cells. Notably, ExoSND1-KO, lacking CD47, were preferentially phagocytosed by macrophages, triggering M1 reprogramming via exosome-derived dsDNA activation of the cGAS-STING/TBK1/NF-κB pathway. This process led to increased secretion of inflammatory cytokines (IL-1β, IL-6, TNF-α) and activation of type I cell-mediated immunity. Our study suggests that targeting SND1 enrichment in tumor cells could be a promising strategy to inhibit tumor metastasis.