Hypoxia-Driven Immune Escape in Clear Cell Renal Cell Carcinoma: A Prognostic Model and Dual-Functional Biomarker...

For patients with recurrent or metastatic clear cell renal cell carcinoma (ccRCC), immunotherapy has demonstrated substantial antitumor activity. However, accurately predicting which patients will benefit from these therapies remains a major challenge. This study aims to elucidate the regulatory role of the hypoxic tumor microenvironment in immune suppression and immune escape, to develop a hypoxia-based prognostic model, and to identify key biomarkers to guide personalized treatment decisions. We applied weighted gene co-expression network analysis (WGCNA) to screen hypoxia-related genes and constructed a hypoxia risk score (HRS) model using LASSO-Cox regression. We found that the HRS model effectively predicted immunotherapy response and prognosis, with patients in the high-HRS group exhibiting significantly shorter overall survival. A high HRS was associated with immune escape by reshaping the T-cell-infiltrated tumor microenvironment (TME), and showed strong positive correlations with cancer-immunity cycle activity, PD-L1/CTLA-4 immune checkpoint expression, and T-cell inflammation scores. Importantly, cell-based and animal experiments demonstrated that PLOD2, a key gene in the HRS model, plays a critical role in hypoxia-induced immune escape in ccRCC. PLOD2 significantly promoted ccRCC cell growth and migration in vitro and in vivo. High PLOD2 expression in clinical samples was associated with ccRCC progression and potentially enhanced sensitivity to immunotherapy by modulating tumor mutational burden and immune escape-related pathways. In summary, our study successfully constructed an HRS model to predict the efficacy of immune checkpoint inhibitor (ICI)-based immunotherapy. PLOD2 was identified as a dual-functional biomarker with both prognostic and predictive value for immunotherapy. The HRS model provides a quantitative tool for immunotherapy stratification. Notably, high PLOD2 expression indicates tumor progression yet paradoxically associates with enhanced immunotherapy response through activation of immune escape pathways, thereby offering a potential therapeutic target for converting "cold tumors" into "hot tumors".