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Objective The latest research proposed a novel copper-dependent programmed cell death named cuproptosis. We aimed to elucidate the influence of cuproptosis in clear cell renal cell carcinoma (ccRCC) from a multi-omic perspective. Methods This study systematically assessed mRNA expression, methylation, and genetic alterations of cuproptosis genes in TCGA ccRCC samples. Through unsupervised clustering analysis, the samples were classified as different cuproptosis subtypes, which were verified through NTP method in the E-MTAB-1980 dataset. Next, the cuproptosis score (Cuscore) was computed based on cuproptosis-related genes via PCA. We also evaluated clinical and immunogenomic features, drug sensitivity, immunotherapeutic response, and post-transcriptional regulation. Results Cuproptosis genes presented multi-layer alterations in ccRCC, and were linked with patients’ survival and immune microenvironment. We defined three cuproptosis subtypes [C1 (moderate cuproptosis), C2 (low cuproptosis), and C3 (high cuproptosis)], and the robustness and reproducibility of this classification was further proven. Overall survival was best in C3, moderate in C1, and worst in C2. C1 had the highest sensitivity to pazopanib, and sorafenib, while C2 was most sensitive to sunitinib. Furthermore, C1 patients benefited more from anti-PD-1 immunotherapy. Patients with high Cuscore presented the notable survival advantage. Cuscore was highly linked with immunogenomic features, and post-transcriptional events that contributed to ccRCC development. Finally, several potential compounds and druggable targets (NMU, RARRES1) were selected for low Cuscore group. Conclusion Overall, our study revealed the non-negligible role of cuproptosis in ccRCC development. Evaluation of the cuproptosis subtypes improves our cognition of immunogenomic features and better guides personalized prognostication and precision therapy.

How to maximize the targeted accumulation of nanomedicine is still the goal of scientists. Using artificial intelligence technology to develop nanosystems with active targeting capabilities to promote effective drug delivery is an excellent tumor targeting therapy strategy. It is reported that ferroptosis therapy has a significant therapeutic effect on migratory breast cancer. In this study, we constructed a comprehensive ferroptosis treatment strategy for multiple target intervention of migratory breast cancer by combining magnetically driven and exosome-mediated tumor double-targeting complex nanovesicles (A15-THP-1exo(SPION/Sor)) with active targeting and passive targeting transport modes. The complex nanovesicles contain a functional exosome with high expression of A15 protein, which is used to mediate the nanovesicles to achieve the active tumor targeting effect; superparamagnetic nanoparticles can not only mediate the passive targeting of tumor by nanovesicles but also act as an inducer of ferroptosis. To implement multi-target intervention to maximize the therapeutic effect of ferroptosis by complex nanovesicles, the ferroptosis inducer sorafenib and iron supplement magnetic nanoparticles were combined. Ferroptosis is enhanced by blocking the xCT/GSH/GPX-4 system and increasing iron supply. The results in vivo and in vitro showed that the complex nanovesicles had significant tumor targeting and had an excellent ferroptosis treatment effect on migratory breast cancer.