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This carcinoma is distinguished by its abundant cytoplasmic mucinous cells and aggressive clinical behavior, often affecting younger individuals and leading to a poor prognosis due to its advanced\u2010stage presentation and resistance to standard treatments. A critical factor in its progression is the tumor's uniquely immunosuppressive and stromal\u2010rich microenvironment, characterized by dysfunctional immune infiltrates, activation of cancer\u2010associated fibroblasts, extracellular matrix remodeling, and complement cascade dysfunction. Recent research has highlighted the significance of key biomarkers, including MSMB, AGR2, CLDN18.2, and notably GRIN2D, which play roles in tumor angiogenesis, immune evasion, and metabolic reprogramming. The interaction of these elements contributes to therapeutic resistance and immune escape, thereby reducing the effectiveness of chemotherapy and checkpoint inhibitor immunotherapies. Innovative strategies that integrate stromal\u2010targeting agents, complement modulators, anti\u2010CLDN18.2 antibodies, and novel GRIN2D\u2010targeted therapies, along with precision molecular profiling, offer potential for enhancing patient outcomes. Tailored approaches that incorporate early detection and dynamic biomarker monitoring may ultimately transform GSRCC management toward personalized, evidence\u2010based therapies and prevention.<\/jats:p>","DOI":"10.1111\/cts.70424","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T09:12:11Z","timestamp":1763457131000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Gastric Signet Ring Cell Carcinoma: Tumor Microenvironment Reprogramming and Novel Therapeutic Targets With Emphasis on\n                    <scp>GRIN2D<\/scp>"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2232-7065","authenticated-orcid":false,"given":"Dipali","family":"Raju","sequence":"first","affiliation":[{"name":"Department of Surgical Oncology Manipal Comprehensive Cancer Care Center, Kasturba Medical College, Manipal Academy of Higher Education  Manipal Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0742-5373","authenticated-orcid":false,"given":"Swathi","family":"Prabhu","sequence":"additional","affiliation":[{"name":"Division of Oncopathology, Department of Pathology Kasturba Medical College, Manipal Academy of Higher Education  Manipal Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8145-885X","authenticated-orcid":false,"given":"Anjal","family":"Maria","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Kasturba Medical College, Manipal Academy of Higher Education  Manipal Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7882-6745","authenticated-orcid":false,"given":"Shriya Narendra Shet","family":"Shirodkar","sequence":"additional","affiliation":[{"name":"Department of Nephrology Kasturba Medical College, Manipal Academy of Higher Education  Manipal Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6815-0097","authenticated-orcid":false,"given":"Rama Rao","family":"Damerla","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Kasturba Medical College, Manipal Academy of Higher Education  Manipal Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6018-8098","authenticated-orcid":false,"given":"Sanjiban","family":"Chakrabarty","sequence":"additional","affiliation":[{"name":"Department of Public Health Genomics Manipal School of Life Sciences, Manipal Academy of Higher Education  Manipal Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9930-5020","authenticated-orcid":false,"given":"Preethi S.","family":"Shetty","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology Manipal Comprehensive Cancer Care Center, Kasturba Medical College, Manipal Academy of Higher Education  Manipal Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3322-5399","authenticated-orcid":false,"given":"Mahadev","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice Medical College of Pharmaceutical Sciences, Manipal Academy of Higher Education  Manipal Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1759-1500","authenticated-orcid":false,"given":"Naveena A. 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