Brain abundant membrane attached signal protein 1 regulates macrophage polarization through EGFR/PI3K/AKT signaling in renal cell carcinoma.

BACKGROUND

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer, accounting for approximately 80 % of cases and contributing to the highest mortality rate among renal cancers.

METHODS

The TCGA database and WGCNA were used to identify key genes that mediate the immunosuppressive microenvironment. Single-cell transcriptomics was employed to determine cellular localization and cell-to-cell Interaction. Macrophages phenotypes were assessed using WB, qRT-PCR, and flow cytometry. AAV was used for gene silencing in a mouse model to investigate the in vivo role of BASP1 in macrophages.

RESULTS

High expression of Brain abundant membrane attached signal protein 1(BASP1) is associated with immunosuppression, poor response to ICI, and abnormal accumulation of macrophages. In renal cancer, BASP1 is predominantly expressed in macrophages, particularly in M2 macrophages, and is linked to abnormal activation of the EGFR and PI3K/AKT signaling pathways. Silencing BASP1 reduces macrophage polarization towards the M2 phenotype. Mechanistically, BASP1 enhances EGFR expression, leading to increased activation of the downstream PI3K/AKT pathway, thereby driving M2 macrophage polarization. In an intracranial homograft model, AAV-shBASP1 significantly inhibited tumor growth and reduced M2 TAM infiltration.

CONCLUSIONS

This study demonstrates that BASP1 promotes macrophage polarization by activating the EGFR/PI3K/AKT pathway, thereby facilitating tumor progression.