Targeted degradation of ATP7B via a novel autophagy-targeting chimera promotes cuproptosis to potentiate anti-tumor immunity in clear cell renal cell carcinoma.

Cuproptosis, a recently identified form of regulated cell death, holds therapeutic promise in cancer. However, the mechanisms governing copper homeostasis and their impact on the immune landscape of clear cell renal cell carcinoma (ccRCC) remain poorly understood. A cuproptosis-related risk model was constructed to identify key prognostic factors. The role of ATP7B in ccRCC was validated using clinical cohorts, in vitro assays, and xenograft models. Mechanistic studies including Co-IP, ubiquitination assays, and Western blot were employed to elucidate the RNF186-p62-ATP7B axis. An autophagy-targeting chimera (ATAUTAC) was developed to evaluate its therapeutic and immunomodulatory potential. High ATP7B expression correlated with poor prognosis and immune evasion in ccRCC. We found that the E3 ligase RNF186 catalyzes K63-linked ubiquitination of ATP7B, driving its selective autophagic degradation via the receptor p62. In ccRCC, RNF186 downregulation leads to ATP7B accumulation, thereby limiting copper-induced proteotoxic stress. Our developed ATAUTAC effectively degraded ATP7B, disrupted mitochondrial TCA cycle metabolism, and induced canonical cuproptosis. Combining ATAUTAC with anti-PD-1 therapy significantly suppressed tumor growth and prolonged survival in vivo. Mechanistically, ATAUTAC-induced metabolic remodeling was accompanied by PD-L1 downregulation, enhanced CD8+ T-cell infiltration, pro-inflammatory cytokine release, and a shift of macrophages toward an M1-like anti-tumor phenotype. This study identifies the RNF186-p62-ATP7B axis as a critical regulator of copper homeostasis in ccRCC. Targeting ATP7B via ATAUTAC offers a potent strategy to induce cuproptosis and sensitize ccRCC to immunotherapy.