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Background Gastroesophageal cancer is a leading cause of cancer-related mortality worldwide, with existing treatment options offering limited benefits to patients with advanced disease. This is partly due to the immunosuppressive tumor microenvironment, characterized by a predominance of anti-inflammatory macrophages that support tumor growth. However, macrophages retain the capacity to mediate potent anti-tumor effects when properly activated. Bispecific antibodies that redirect macrophages to recognize and phagocytose cancer cells have emerged as a promising therapeutic approach. Here, we developed a high-throughput platform to rapidly generate and screen bispecific antibodies designed to robustly engage macrophages for targeted elimination of gastroesophageal cancer cells.Methods We selected a panel of eight gastroesophageal cancer cell lines representing diverse mutational profiles and varying levels of HER2 expression. A comprehensive library of clinically relevant monoclonal antibodies targeting cell surface proteins frequently expressed in gastroesophageal cancers was screened for binding affinity and capacity to induce macrophage-mediated cytotoxicity in vitro. Antibodies that elicited robust macrophage activation were reformatted into single-chain variable fragment Fc (scFv-Fc) constructs engineered with knob-into-hole mutations to facilitate heterodimeric bispecific antibody formation. A matrix of 77 novel bispecific scFv-Fcs was generated and evaluated for macrophage recruitment and tumor cell killing. Lead candidates are being advanced to in vivo efficacy testing using mouse xenograft models of gastroesophageal cancer.Results Screening revealed that seven of eight cell lines expressed high levels of CD47, a key macrophage inhibitory checkpoint, while EGFR, FGFR2, HER2, and TROP2 were the most frequently expressed tumor-associated antigens. Most cell lines demonstrated susceptibility to anti-CD47-mediated macrophage killing, with a modest correlation between CD47 expression and efficacy. Antibodies targeting highly expressed tumor antigens exhibited strong anti-tumor activity, with synergy observed when combined with anti-CD47. Among the 77 bispecific scFv-Fcs generated, several demonstrated potent macrophage engagement and tumor cell killing. The top-performing bispecific antibodies—CD47×FGFR2b, CD47×TROP2, and HER2×FGFR2b—were purified at scale and showed IC 5 0 values ranging from 50 to 200 ng/mL in macrophage cytotoxicity assays. Interestingly, HER2×FGFR2b bispecific antibodies retained efficacy across cell lines with variable expression of either target, suggesting broad therapeutic potential and the ability to benefit a larger subset of patients.Conclusions By integrating antibody library screening with bispecific antibody engineering, we established a platform capable of rapidly identifying potent macrophage-engaging bispecific antibodies targeting gastroesophageal cancer. Lead candidates show strong in vitro efficacy and are progressing to in vivo evaluation. These findings support further development of macrophage-directed bispecific antibodies as a promising immunotherapeutic strategy for patients with advanced gastroesophageal cancer.