Abstract New clinical opportunities are needed to increase immunotherapy (IT) benefit. Whereas IFNγ-pathway mutations cause IT resistance, we find that IFNγ receptor-deficient tumors remain remarkably susceptible to T-cell elimination. By integrating transcriptomics, proteomics and genome-wide CRISPR-Cas9 screening with clinical data, we defined the IFNγ-independent tumor landscape and uncovered an immunotherapeutic opportunity. Ablation of TRAF2 enhanced T-cell elimination of both melanoma and lung cancer cells by redirecting TNF signaling to favor RIPK1-dependent apoptosis. TRAF2 loss greatly enhanced the therapeutic potential of pharmacologic inhibition of its interaction partner cIAP. Corroborating these observations clinically, we identified recurring TRAF2 mutations that reduced T-cell sensitivity of tumor cells. Furthermore, both IT response duration and overall survival were lower for tumors that had acquired TNF pathway mutations on IT, suggesting immune-editing by TNF pressure. These results functionally annotate the tumor genome landscape of IFNγ-independent T-cell cytotoxicity, and merit clinical exploration of TRAF2 for cancer immunotherapy. Citation Format: Daniel S. Peeper, David Vredevoogd, Thomas Kuilman. T-cell-induced tumor vulnerability discovery in an IFNγ-independent genomic landscape [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B033.