Abstract Background: Immune checkpoint blockade has improved outcomes in several cancers, but tumors with strongly immunosuppressive microenvironments, such as microsatellite-stable colorectal cancer (MSS-CRC), pancreatic cancer, and many hepatocellular carcinomas (HCCs), remain largely unresponsive. These tumors exhibit immune exclusion, impaired innate effector function, and dense tumor-supportive stroma. TM4SF5, a four-pass transmembrane glycoprotein enriched in gastrointestinal cancers, has been implicated in exclusion of effector lymphocytes, NK-cell dysfunction, and recruitment of tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), suggesting a central role in establishing an immunosuppressive tumor microenvironment (TME). Methods: A first-in-class monoclonal antibody was developed against native TM4SF5, recognizing the conformational extracellular epitope to disrupt TM4SF5-mediated signaling and immune-suppressive functions. Full-length TM4SF5 was reconstituted into a virus-like lipoparticle to maintain its native membrane conformation, enabling selection of TM4SF5-specific antibodies. A lead clone with high-affinity binding to both human and mouse TM4SF5 was Fc-optimized to generate the candidate RCT1213. RCT1213 was evaluated in vitro and in vivo for anti-tumor efficacy using patient-derived xenograft (PDX) tumor samples and TM4SF5-positive MSS-CRC cell line xenograft, respectively. Combination studies with immune checkpoint inhibitors (ICIs) assessed therapeutic interactions. Results: RCT1213 bound TM4SF5 with high affinity and attenuated TM4SF5-driven suppressive signaling in vitro PDX-derived tumors. Treatment with RCT1213 restored NK-cell activation and cytotoxic function, consistent with reversal of TM4SF5-mediated innate immune suppression. In MSS-CRC xenograft models, RCT1213 inhibited tumor growth and remodeled the TME, increasing immune-cell infiltration while reducing suppressive stromal and myeloid components. Combination therapy with ICIs yielded superior tumor control compared with either agent alone. Conclusion: Targeting TM4SF5 with RCT1213 alleviates TM4SF5-driven immunosuppression and restores innate effector function, resulting in robust anti-tumor activity in MSS-CRC models. These findings position TM4SF5 as an upstream immune-modulatory target and support RCT1213 as a first-in-class therapeutic candidate. IND-enabling studies are underway to advance RCT1213 into clinical development for MSS-CRC and other TM4SF5-expressing solid tumors. Citation Format: Unbyeol Goh, Sujin Kim, Hong Sook Kim, Yong-Bae Kim. Gastrointestinal tumor-associated target: A first-in-class therapeutic monoclonal antibody abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4057.
Goh et al. (Fri,) studied this question.