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Hyperactivated Wnt signaling is a key driver in cancers such as colorectal cancer and pancreatic ductal adenocarcinoma, but its direct inhibition is limited by severe toxicities due to the importance of Wnt signaling in normal tissues, particularly the gut and bone. To address this challenge, we designed bispecific antibodies that selectively target surface proteins of oncogenic signaling pathways in tumor cells while sparing normal cells. Using single-cell technologies, we identified tumor-specific receptors, including tumor-associated calcium signal transducer 2 (TROP2), which are absent in cells reliant on Wnt signaling. Our TROP2-targeted anti-Frizzled bispecific antibody effectively inhibited Wnt signaling in preclinical models with minimal effect on normal intestinal tissue. Expanding this approach, we developed tumor-targeted, toxicity-sparing bispecific antibodies against fibroblast growth factor receptor 1 (FGFR1) and epidermal growth factor receptor (EGFR). This work establishes a framework for designing targeted therapeutics that minimize cell type\u2013specific toxicities in cancer and other diseases.<\/jats:p>","DOI":"10.1126\/sciadv.adx3959","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T17:58:41Z","timestamp":1779472721000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["Tumor-targeted bispecific antibodies effectively inhibit oncogenic pathways while minimizing toxicity"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8057-2564","authenticated-orcid":true,"given":"Yvonne T.","family":"Kschonsak","sequence":"first","affiliation":[{"name":"Department of Research Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Ching","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of 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