Complement C3a receptor expression is associated with distinct immune microenvironmental profiles in clear cell renal cell carcinoma

The complement receptor C3aR has emerged as an important regulator of tumor–immune interactions in several solid cancers. However, its cellular distribution and relationship with the immune microenvironment in clear cell renal cell carcinoma (ccRCC) remain poorly understood. Here, we investigated the expression pattern, cellular distribution and immune context of C3aR in human ccRCC. Transcriptomic analyses of the TCGA-KIRC cohort combined bulk RNA-sequencing correlations, immune-cell deconvolution, and composition-adjusted partial correlations. C3AR1 cellular distribution was independently assessed using a publicly available ccRCC single-cell RNA-sequencing dataset. C3aR protein expression was then assessed by immunohistochemistry in an independent cohort of 70 patients with ccRCC and correlated with clinicopathological features and immune cell infiltration. Double immunohistochemistry and unsupervised immune clustering were used to characterize the cellular and microenvironmental context of C3aR expression. In TCGA-KIRC, C3AR1 was associated with macrophage/antigen-presenting-cell genes and CD4 after adjustment for inferred immune-cell abundance. Single-cell analysis localized C3AR1 predominantly to the myeloid compartment and showed heterogeneous expression across myeloid states; among C3AR1 + myeloid cells, 98% co-expressed CD68 , 68% CD163 , and nearly all HLA-DRA , whereas only approximately half of marker + cells expressed C3AR1 . In the independent IHC cohort, C3aR + cell density was modestly higher in localized tumors and positively correlated with CD4 + T-cell infiltration, while inversely correlated with CD68 + macrophage density. Immune clustering identified three profiles with increasing tumor aggressiveness and progressively lower C3aR + cell density. C3AR1 was not independently associated with survival outcomes in TCGA-KIRC. Together, these findings identify C3aR as a marker of a specific myeloid-associated immune context in ccRCC rather than a surrogate of total macrophage abundance, and link its expression to distinct immune microenvironmental profiles across disease states.