2026-10-13T03:36:23Z https://www.scidb.cn/oai

10.57760/sciencedb.42483 2026-07-09T14:56:38Z

2026-07-09 Integrative Single-Cell and Spatial Transcriptomic Analyses Identify a PTGS2–EGFR/ERBB2–CCND1 Axis Driving Immunotherapy Resistance in Clear Cell Renal Cell Carcinoma doi:10.57760/sciencedb.42483 en Immune checkpoint blockade has reshaped the therapeutic landscape of clear cell renal cell carcinoma (ccRCC), yet a substantial proportion of patients fail to achieve durable clinical benefit. The cellular programs and targetable mechanisms underlying immunotherapy non-benefit remain incompletely defined. Here, we integrated patient-derived single-cell RNA sequencing data from ccRCC with bulk RNA-seq profiles of immunotherapy-treated patients using the Scissor algorithm, enabling the classification of tumor-associated cells into clinically beneficial and non-beneficial states. Trajectory inference and cell–cell communication analyses identified a CCND1-high cellular program enriched in the clinical non-benefit group. Mechanistically, CCND1 was linked to PTGS2-associated EGFR/ERBB2 signaling, and notably, PTGS2-associated signaling was mainly derived from C1q+ macrophages. CCND1 showed coordinated expression with TMSB10 and NDUFA4L2, suggesting its association with epithelial–mesenchymal transition and oxidative phosphorylation-related programs. 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). ccRCC; immunotherapy; PTGS2; CCND1; EMT; OXPHOS Xiaochen Qi Guangzhen Wu RESTRICTED dataset Science Data Bank