Disulfidptosis as an immunometabolic rheostat in gastrointestinal cancers: tuning the balance between T Cell exhaustion and immunogenic cell death.

Disulfidptosis is a recently characterized regulated cell death pathway driven by disulfide stress. However, its immunological consequences in the tumor microenvironment remain poorly defined. In this review, we propose a conceptual framework in which disulfidptosis functions as an immunometabolic rheostat, wherein the net outcome-T cell exhaustion versus immunogenic cell death-is critically dependent on stress intensity, kinetics, and cellular context. We hypothesize that in glucose-deprived gastrointestinal tumors, chronic sub-lethal disulfide stress may erode CD8+ T cell effector function through F-actin crosslinking at the immunological synapse, potentially involving STAT3-LDHB-G6PD-driven transcriptional reprogramming toward a TOX-associated exhaustion state. Conversely, acute synchronous tumor lysis releases damage-associated molecular patterns (DAMPs); however, productive dendritic cell (DC) cross-presentation requires that adenosine triphosphate (ATP)/adenosine conversion and high mobility group box 1 (HMGB1) redox state meet quantitative thresholds. The DPP7-GPX4 axis suppresses disulfidptosis to limit DAMP release and facilitate natural killer (NK) cell evasion, positioning it as a candidate innate immune checkpoint. We advance testable predictions for tuning this rheostat via timed nanodelivery, dietary sensitization, and DPP7/GPX4 targeting, while explicitly distinguishing correlative biomarkers from causal mechanisms. Priority experiments to validate-or falsify-the rheostat hypothesis are outlined.