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Accessory file for ENA Project: PRJEB102638. Enhancing the specificity of oncogenic pathway inhibition in cancer cells improves both efficacy and tolerability of anti-cancer therapies. Hyperactivated Wnt signaling is a key driver in cancers such as CRC and PDAC, but its direct inhibition is limited by severe toxicities due to the importance of Wnt signalling 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 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 FGFR1 and EGFR. This work establishes a framework for designing targeted therapeutics that minimize cell-type-specific toxicities in cancer and other diseases.