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Advances in cancer biology have identified vulnerabilities amenable to precision oncology approaches including antibody drug conjugates (ADCs). In theory, ADCs combine specificity of cancer cell receptor antibody targeting with potent cytotoxins. However, toxicities and resistance limit ADC clinical efficacy. Delivering ADCs with radiotherapy can improve their therapeutic index. Here, the combination of ADC payloads (anti\u2010tubulin monomethyl auristatin E (MMAE) or topoisomerase I inhibitors DXd and SN\u201038) with radiotherapy is reported in immune\u2010competent murine models. To directly compare ADC payload effects and remove targeting bias, the payloads are tested as free drugs and as tumor\u2010targeted ADC or peptide\u2010drug conjugates in combination with ionizing radiation. Both DXd and MMAE induce anti\u2010tumor immune response that block re\u2010challenge tumor growth. As monotherapy, DXd is more potent than MMAE at inhibiting tumor formation. In contrast when combined with ionizing radiation at subtherapeutic doses, MMAE but not DXd radiosensitizes resulting in improved tumor control and greater immune activation with MMAE. The differential effects of anti\u2010tubulin versus topoisomerase I inhibitors when combined with ionizing radiation and immunotherapies can inform and optimize clinical development of ADC based chemo\u2010radio\u2010immunotherapy combinations for cancer patients.<\/jats:p>","DOI":"10.1002\/advs.202506552","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T12:49:11Z","timestamp":1761310151000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Interactions of Antibody Drug Conjugate Anti\u2010Tubulin and Topoisomerase I Inhibitor Payloads with Radiotherapy to Potentiate Immunotherapy"],"prefix":"10.1002","volume":"13","author":[{"given":"Jacqueline","family":"Lesperance","sequence":"first","affiliation":[{"name":"Department of Radiation Medicine and Applied Sciences University of California San Diego  La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan S.","family":"Yung","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of California San Diego  La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael M.","family":"Allevato","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of California San Diego  La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus M","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Radiation Medicine and Applied Sciences University of California San Diego  La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria F.","family":"Camargo","sequence":"additional","affiliation":[{"name":"Department of Radiation Medicine and Applied Sciences University of California San Diego  La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Saddawi\u2010Konefka","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery University of California San Diego  La Jolla CA 92093 USA"},{"name":"Moores Cancer Center  La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanika","family":"Dhawan","sequence":"additional","affiliation":[{"name":"Department of Radiation Medicine and Applied Sciences University of California San Diego  La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashwyn K.","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Surgery University of California San Diego  La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahsa","family":"Mortaja","sequence":"additional","affiliation":[{"name":"Department of Radiation Medicine and Applied Sciences University of California San Diego  La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Bice","sequence":"additional","affiliation":[{"name":"Department of Human Oncology University of Wisconsin  Madison WI 53705 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Scanderbeg","sequence":"additional","affiliation":[{"name":"Department of Radiation Medicine and Applied Sciences University of California San Diego  La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Alvarado","sequence":"additional","affiliation":[{"name":"Celldex Therapeutics  Hampton NJ 08827 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jyoti","family":"Mayadev","sequence":"additional","affiliation":[{"name":"Department of Radiation Medicine and Applied Sciences University of California San Diego  La Jolla CA 92093 USA"},{"name":"Moores Cancer Center  La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramez N.","family":"Eskander","sequence":"additional","affiliation":[{"name":"Moores Cancer Center  La Jolla CA 92093 USA"},{"name":"Division of Gynecologic Oncology Department of Obstetrics Gynecology and Reproductive Sciences University of California San Diego  La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen R.","family":"Adams","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of California San Diego  La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pippa F.","family":"Cosper","sequence":"additional","affiliation":[{"name":"Department of Human Oncology University of Wisconsin  Madison WI 53705 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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