Integrative Single-Cell and Spatial Transcriptomic Analyses Identify a PTGS2–EGFR/ERBB2–CCND1 Axis Driving Immunotherapy Resistance in Clear Cell Renal Cell Carcinoma

Functional experiments demonstrated that CCND1 promoted the viability of ccRCC cells and supported the activation of the PTGS2–EGFR/ERBB2–CCND1 regulatory axis. Spatial transcriptomic analysis further confirmed the spatial presence of this axis and revealed co-localization of CCND1 with TMSB10-associated EMT features and NDUFA4L2-associated OXPHOS features within tumor regions, along with the spatial proximity of C1q+ macrophages expressing PTGS2.

Importantly, pharmacological inhibition of PTGS2 by celecoxib suppressed the PTGS2–EGFR/ERBB2–CCND1 axis and enhanced the therapeutic efficacy of anti-PD-1 treatment in vivo. Collectively, our study defines a CCND1-centered immunotherapy non-benefit program in ccRCC and identifies PTGS2 inhibition as a potential strategy to overcome resistance to anti-PD-1 therapy. These findings provide a single-cell and spatially resolved framework for understanding immunotherapy failure and support the rational combination of celecoxib with immune checkpoint blockade in ccRCC.Code, original experiment data, single cell data(Rdata).