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With half of patients progressing to recurrent or metastatic disease, alternative therapeutic strategies are urgently needed. Antibody\u2010drug conjugates (ADCs) offer promise, but their clinical impact requires identification of robust target antigens and elucidation of resistance mechanisms. Through single\u2010cell transcriptomic analysis followed by experimental validation, we identified TROP2 as a consistently and highly overexpressed cell\u2010surface antigen in HNSCC and ESCA. DS\u20101062a, a TROP2\u2010directed ADC delivering the camptothecin (CPT)\u2010like topoisomerase I inhibitor deruxtecan (Dxd), demonstrated marked tumor regression in HNSCC and ESCA xenografts. This pronounced sensitivity may be attributable to prevalent homologous recombination deficiency (HRD) in these cancers, conferring vulnerability to DNA single\u2010strand break (SSB)\u2010inducing agents such as PARP inhibitors. However, therapeutic potential is constrained by an incomplete understanding of the regulators of drug sensitivity. To systematically dissect genetic modifiers of SSB\u2010induced cytotoxicity, we performed a genome\u2010wide CRISPR\/Cas9 sgRNA knockout screen and identified AUNIP as a determinant of chemosensitivity. AUNIP loss profoundly enhanced DS\u20101062a cytotoxicity and multiple SSB\u2010inducing chemotherapies across diverse HNSCC and ESCA models. Mechanistically,\n                    <jats:italic>AUNIP<\/jats:italic>\n                    deficiency led to impaired DNA repair, attenuated stress response signaling, and heightened apoptotic susceptibility. These findings establish TROP2 as a therapeutically actionable target and reveal AUNIP as a genetic rheostat governing ADC and chemotherapy response. Co\u2010targeting AUNIP represents a promising strategy to potentiate SSB\u2010inducing therapies and improve outcomes in patients with squamous carcinomas of the upper aerodigestive tract.\n                  <\/jats:p>","DOI":"10.1002\/mc.70115","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T18:41:31Z","timestamp":1778179291000},"page":"921-937","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting TROP2 and Exploiting AUNIP as a Determinant of ADC Cytotoxicity and Chemosensitivity in HNSCC and ESCA Cancers"],"prefix":"10.1002","volume":"65","author":[{"given":"Jiaqi","family":"Bai","sequence":"first","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery Beijing Friendship Hospital, Capital Medical University Beijing Beijing People's Republic of China"},{"name":"National Institute of Biological Sciences Beijing Beijing 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