CD9-positive tumor-associated macrophages promote renal cell carcinoma progression by activating the orphan nuclear receptor Nor1/Nr4a3

Tumor growth, metastasis, and treatment response in renal cell carcinoma (RCC) are believed to be regulated by the tumor microenvironment (TME). However, the mechanisms underlying the genomic, transcriptomic, and epigenetic alterations in clear cell RCC progression remain incompletely understood. This study analyzed single-cell RNA sequencing data from public databases, including tissue samples from three patients with RCC and three matched pairs of immune cells from tumor tissue and peripheral blood to screen macrophages with differential expression in the TME. We found that a CD9⁺ macrophage population was identified in the RCC tumor tissue, suggesting a role for CD9-expressing macrophages in RCC progression. The function of these macrophages was further investigated through in vitro and in vivo experiments involving CD9 knockdown or overexpression. CD9 expression was elevated in RCC tissues compared to adjacent non-cancerous tissues. CD9 knockdown considerably inhibited the TME-induced macrophages (M2), while CD9-overexpressing macrophages markedly promoted RCC cell growth in vitro and in vivo. Moreover, this phenomenon may be associated with the orphan nuclear receptor NOR1//Nr4a3 activation by CD9. These findings indicated that macrophages in the TME exhibited distinct expression patterns during RCC progression and that CD9⁺ macrophages promoted RCC development, suggesting that CD9 may be a potential therapeutic target for inhibiting RCC progression.