Targeting fitness surveillance restores T-cell immunity and sensitizes solid tumors to immune checkpoint inhibitors

Immune checkpoint inhibitors (ICIs) fail in most solid tumors despite their transformative success in a minority of patients. Here, using integrated human tumor profiling and humanized patient-derived xenograft (PDX) models, we identify Flower-mediated fitness elimination as a dominant, conserved mechanism of T-cell attrition that limits ICI efficacy across epithelial cancers. Stromal compartments in high-grade serous ovarian cancer, non-small-cell lung cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma exhibit high Flower-Lose expressioncoupled to severe CD8⁺ T-cell exclusion. Tumor-infiltrating T-cells themselves acquire a “loser” state marked by elevated Flower-Lose, rendering them vulnerable to competitive elimination by the stromal niche. Across five orthotopic humanized PDX tumor types and three independent cohorts, ICIs alone produced minimal T-cell restoration, persistent metastatic dissemination, and negligible survival benefit (e.g., median ≈42 days). In contrast, pharmacologic blockade of Flower signaling increased intratumoral T-cell density by 5-7-fold (MixedLM P < 10⁻¹⁵), reduced metastatic burden by 54-75%, suppressed tumor growth by >90%, and produced durable survival benefit across all models, with median survival not reached and strong meta-analytic significance (Z = 10.56, P < 10⁻²⁵). Together, these findings reveal Flower-mediated fitness surveillance as a pan-cancer, tissue-level barrier to immunotherapy and establish Flower blockade as a universally effective strategy to restore T-cell persistence and unlock durable ICI responses across historically immune-cold solid tumors.