PD-1 blockade plus tyrosine kinase inhibitor remodels the tumor microenvironment in advanced renal cell carcinoma

The combination of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has improved clinical outcomes in advanced renal cell carcinoma (aRCC), though therapeutic resistance remains a major challenge. We conducted single-cell transcriptomic analysis on 61 tumor samples from 34 aRCC patients treated with TKIs alone or in combination with ICIs. Non-responders exhibited increased neutrophil infiltration and enrichment of SAA+ tumor cells following treatment. We identified a VEGFA+CEACAM1+ neutrophil subset exhibiting immunosuppressive properties that is associated with poor clinical response. In vivo, pharmacologic inhibition of SAA enhanced sensitivity to ICI plus TKI combination therapy, while blockade of the CEACAM1–TIM-3 axis in humanized PD-1 mouse models significantly potentiated anti–PD-1 efficacy. Our study establishes a single-cell atlas of the aRCC tumor microenvironment under treatment pressure and identifies a previously unrecognized SAA–CEACAM1–TIM-3 axis driving drug resistance, highlighting potential targets to improve therapy efficacy. Tyrosine kinase inhibitors (TKIs) combined with immunotherapy have improved outcomes in advanced renal cell carcinoma (aRCC), yet resistance persists. This group presents single-cell transcriptomic profiling of aRCC patients treated with TKIs and immune checkpoint inhibitors, uncovering an immunosuppressive microenvironment linked to therapeutic resistance.