Abstract
The mystery about the mechanistic basis of disulfidptosis has recently been unraveled and shows promise as an effective treatment modality for triggering cancer cell death. However, the limited understanding of the role of disulfidptosis in tumor progression and drug sensitivity has hindered the development of disulfidptosis-targeted therapy and combinations with other therapeutic strategies. Here, we established a disulfidptosis signature model to estimate tumor disulfidptosis status in approximately 10,000 tumor samples across 33 cancer types and revealed its prognostic value. Then, we characterized disulfidptosis-associated molecular features and identified various types of molecular alterations that correlate with both drug-resistant and drug-sensitive responses to anti-tumor drugs. We further showed the vast heterogeneity in disulfidptosis status among 760 cancer cell lines across 25 cancer types. We experimentally validated that disulfidptosis score-high cell lines are more susceptible to glucose starvation-induced disulfidptosis compared to their counterparts with low scores. Finally, we investigated the impact of disulfidptosis status on drug response and revealed that disulfidptosis induction may enhance sensitivity to anti-cancer drugs, but in some cases, it could also lead to drug resistance in cultured cells. Overall, our multi-omics analysis firstly elucidates a comprehensive profile of disulfidptosis-related molecular alterations, prognosis, and potential therapeutic therapies at a pan-cancer level. These findings may uncover opportunities to utilize multiple drug sensitivities induced by disulfidptosis, thereby offering practical implications for clinical cancer therapy.