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The rapid development of ICI-based immunotherapy has ushered in a promising era for clear cell renal cell carcinoma (ccRCC). However, durable clinical responses remain limited to a subset of patients. Therefore, identifying novel predictive biomarkers and developing effective combination immunotherapies are critical for advancing personalized ccRCC management. In this study, we report that ccRCC patients exhibiting elevated ACOX2 expression may benefit from PARPi in combination with ICI. Multi-omics cohorts show ACOX2 is significantly downregulated in ccRCC and correlated with improved clinical prognosis. ACOX2 inhibits the growth of ccRCC both in vitro and in vivo. Mechanistically, ACOX2 interacts with MRE11 and inhibits the binding of MRE11 and RAD50, thereby destabilizing the MRE11-RAD50-NBS1 (MRN) complex. Furthermore, ACOX2 activates the cGAS-STING pathway, correlates with more mature tertiary lymphoid structures (TLS), and enhances CD8⁺ T cell infiltration and activity. Therapeutically, preclinical ccRCC models with high ACOX2 expression, including ccRCC cells, cell-derived xenograft (CDX), patient-derived organoid (PDO), patient-derived xenograft (PDX), and immunocompetent mouse models show increased sensitivity to PARPi plus anti-PD-1 therapy. In conclusion, our findings elucidate a pivotal role of ACOX2 in inhibiting HRR and propose that PARPi, either alone or in combination with anti-PD-1 therapy, represents a promising treatment strategy for ccRCC with elevated ACOX2 expression.

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The online version contains supplementary material available at 10.1186/s12943-025-02420-9.