Intracellular C1r impacts tumor progression and immune microenvironment in renal cancer

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Metastasis and resistance to therapy are major drivers of cancer-related mortality. Complement component C1R is overexpressed in multiple tumor types and correlates with poor prognosis and lack of response to immunotherapy, particularly in clear cell renal cell carcinoma (ccRCC), the most common renal cancer. In several models, C1R knockout reduces proliferation, viability, and migration of cancer cells, suggesting critical cell-intrinsic functions. However, the underlying mechanisms remain poorly understood. We aimed to investigate whether and how C1r contributes to the hallmarks of cancer We used gene silencing, phenotype profiling, RNA-seq, and metabolomics in C1r-expressing ccRCC cell lines (A498, Caki-1) and fibroblasts (BJ) to study C1r function. Findings were corroborated using snRNA-seq data ccRCC patients, including cancer cells and cancer-associated fibroblasts (CAFs). Subcellular fractionation and multiplexed immunofluorescence were used to localize C1r, and co-immunoprecipitation with mass spectrometry identified candidate interactors. A 40-marker immunofluorescence panel was applied to ccRCC tumor sections (n = 6), and a larger patient cohort was stained with an 8-plex panel targeting C1r, stromal and immune cell markers. C1R expression was primarily detected in tumor cells and CAFs in ccRCC. Silencing C1R in vitro impaired proliferation, migration, viability, and sphere formation in both cancer cells and fibroblasts. This phenotype could not be rescued by adding purified C1r, indicating a non-canonical, intracellular role. C1r localized to organelles and nuclei in vitro and in situ . Proteomic analysis identified ~30 candidate interactors related to proliferation and migration. Transcriptomic and metabolic analyses of siC1R cells confirmed altered pathways involved in cell cycle, migration, energy and aminoacid metabolism. C1r levels also influenced immune signaling: C1R knockdown reduced inflammatory signatures in vitro , while its overexpression in tumors correlated with altered T cell infiltration in both RNA-seq and hyperplex imaging data. The relationship between C1r expression and immune cell phenotype is currently under investigation in a patient cohort Our findings reveal novel intracellular functions of C1r in tumor cells and CAFs, independent of the classical complement pathway. These results highlight C1r as a multifunctional, cell-autonomous regulator of tumor progression and immune contexture, and support its potential as a therapeutic target in cancers expressing C1r.

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