{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T05:49:34Z","timestamp":1782107374316,"version":"3.54.5"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Gastric cancer (GC) remains a leading cause of cancer-related death worldwide, and PD-1 monotherapy offers limited clinical benefit due to intrinsic and acquired immune tolerance. PD-1-containing bispecific antibodies (BsAbs) represent an emerging immunotherapeutic strategy to reverse immune suppression, enhance antitumor immunity, and overcome therapy resistance. Here, we present a systematic clinical trial landscape analysis to characterize the global development of PD-1-based BsAbs for GC. We identified 121 interventional clinical trials registered up to April 17, 2026, from the INFORMA database. Total trial numbers grew continuously from 2017 to 2025, with phase II trials constituting the largest segment. The most frequent non-PD-1 cotarget was CTLA-4, followed by VEGF, TIGIT, and LAG3. Most trials combined BsAbs with chemotherapy, focused on stage III\/IV GC, and were conducted in the first-line or neoadjuvant setting. Academic institutions sponsored the majority of trials, and 84.30% were performed in China. Further temporal regression revealed annual growth for CTLA-4, VEGF and TIGIT-targeted programs, and correlation analyses indicated divergent co-target preferences across distinct sponsors and trial status and combination therapy. Subgroup comparison identified that combination therapy was more common in China-led trials, whereas monotherapy was preferentially adopted in non-China-led trials. This Perspective delineates a rapidly expanding global pipeline with China as the leading contributor. Our findings support the rational design of PD-1 BsAbs and combination strategies to target immune tolerance in GC, and highlight future priorities including balancing therapeutic efficacy against safety risks, biomarker-driven patient stratification, and international collaboration to optimize immunotherapy.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1866067","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T05:40:19Z","timestamp":1782106819000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The global clinical trial landscape of PD-1-containing bispecific antibodies for gastric cancer: current status and future directions of targeting immune tolerance"],"prefix":"10.3389","volume":"17","author":[{"given":"Ziyue","family":"Sha","sequence":"first","affiliation":[{"name":"Department of Immunology and Rheumatology, The Fourth Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengzheng","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The Fourth Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanqing","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Immunology and Rheumatology, The Fourth Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Immunology and Rheumatology, The Fourth Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanjun","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Immunology and Rheumatology, The Fourth 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