A lysosomal cell death pathway sensitizes microsatellite-stable tumors to immune checkpoint blockade-RNA-seq
Microsatellite-stable (MSS) tumors resist immune checkpoint blockade (ICB) in part because their cell death is immunologically silent. Screening 2,573 approved drugs for compounds that both kill tumour cells and license dendritic cell (DC) phagocytosis, we identify tamoxifen and define a lysosome-initiated immunogenic death programme. Independently of oestrogen receptors, tamoxifen engages PAX5 to induce LAMP3, which inhibits PIKfyve; the resulting lysosomal membrane permeabilization releases cathepsins and triggers NINJ1-dependent plasma-membrane rupture and HMGB1 release that engages TLR4 on DCs. Other lysosomotropic drugs kill comparably without eliciting DC engagement, and blocking NINJ1 oligomerization preserves killing while abolishing the immune response. At sub-cytotoxic doses, tamoxifen sensitizes MSS colorectal and pancreatic tumors to PD-1 and CTLA-4 blockade across syngeneic, humanized and patient-derived models. In tamoxifen-treated breast cancers, tumor-cell PAX5 nuclear localization and LAMP3 expression associate with DC and CD8+ T cell infiltration. These findings define a lysosome-to-plasma-membrane rupture axis that couples tumour-cell death to antitumour immunity