PANX2 Suppresses Lung Adenocarcinoma Progression by Inducing Disulfidptosis and Enhancing Antitumor Immunity

ABSTRACT Lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality with limited therapeutic options. Disulfidptosis, a novel cell death modality driven by disulfide stress, represents a promising target, yet its regulation in LUAD is poorly defined. Here, we identify Pannexin 2 (PANX2) as a tumor suppressor in LUAD. Clinically, PANX2 expression is downregulated during tumor progression, and low PANX2 levels correlate with poor prognosis. Functionally, PANX2 overexpression induces disulfidptosis in LUAD cells through two convergent axes: (i) activating NRF2 via Ca 2 + ‐dependent stabilization and nuclear translocation to upregulate SLC7A11, increasing cystine uptake and NADPH consumption; (ii) suppressing G6PD to impair NADPH regeneration, compromising cystine clearance. This dual regulation synergistically depletes NADPH, causes cystine overload, and triggers disulfide crosslinking of cytoskeletal proteins, leading to actin cytoskeleton collapse. Moreover, PANX2 enhances extracellular ATP release, activating P2X7R signaling on immune cells to promote antitumor immune infiltration. In humanized mouse models, PANX2 overexpression suppresses tumor growth—effects reversed by NRF2 knockdown, G6PD overexpression, or P2X7R blockade. Collectively, our findings establish PANX2 as a tumor suppressor linking disulfidptosis to antitumor immunity, offering a dual‐target strategy for LUAD therapy.