Disulfidptosis, a novel form of regulated cell death, involves cytoskeletal collapse due to excessive disulfide bond formation, linking metabolism and reactive oxygen species to potential cancer therapy targets. Recent multi‐omics studies highlight the prognostic value of disulfidptosis‐related gene (DRG) signatures in pan‐cancers; however, the molecular mechanisms underlying their biological functions and therapeutic relevance remain poorly defined. Herein, a DRG score model is constructed using LASSO Cox regression across 33 cancer types, and a nomogram incorporating the DRG score is developed for prognostic prediction. The tumor microenvironment, mutation profiles, and immunotherapy responses are analyzed. The DRG score serves as an independent prognostic factor across cancers, correlating with poor outcomes and malignant features. Glucose deprivation induces disulfidptosis in SLC7A11 ^high cells (high SLC7A11 expression), especially in cancers with a high DRG score, such as ovarian cancer. Silencing INF2 prevents disulfidptosis and decreases susceptibility to irofulven, which can be reversed by GLUT inhibitors. SLC7A11 knockdown reduces disulfidptosis, restores ATP/NADPH levels, and protects the cytoskeleton under glucose deprivation, whereas INF2 knockdown impairs cell migration. Moreover, the DRG scores predict prognosis and therapeutic responses. The SLC7A11‐INF2 axis regulates disulfidptosis, migration, and drug sensitivity, highlighting its potential as a marker of metabolic vulnerability in ovarian cancer.

Chimeric antigen receptor (CAR)–T cell therapies have revolutionized the landscape of cancer treatment, in particular in the context of hematologic malignancies. However, for solid tumors that lack tumor-specific antigens, CAR-T cells can infiltrate and attack nonmalignant tissues expressing the CAR target antigen, leading to on-target, off-tumor toxicity. Severe on-target, off-tumor toxicities have been observed in clinical trials of CAR-T therapy for solid tumors, highlighting the need to address this issue. Here, we demonstrated that targeting the cell adhesion and migration molecules lymphocyte function–associated antigen 1 (LFA-1; CD11a/CD18) and very late activation antigen 4 (VLA-4; CD49d/CD29) with blocking antibodies reduced the on-target, off-tumor toxicity of CAR-T cells in mice. To translate this observation into improved CAR-T cell therapy, we either knocked out both CD11a and CD49d or knocked down CD11a and CD49d along with PSGL1 , another cell adhesion molecule, in CAR-T cells. We found that these modified CAR-T cells exhibited reduced on-target, off-tumor toxicity in vivo without affecting CAR-T cell efficacy. Furthermore, we showed that this approach promoted T cell memory formation and decreased tonic signaling. On the basis of these data, we engineered a human version of these low-toxicity CAR-T cells and further validated the feasibility of this approach in vitro and in vivo. Together, these results provide a potential solution to address the clinical challenge of on-target, off-tumor toxicity in CAR-T therapy.