BACKGROUND: Treatment for initially unresectable/metastatic gastric cancer (UMGC) has traditionally been limited to palliative chemotherapy and supportive care. However, advances in biomarker-driven therapies, particularly dual blockade strategies targeting human epidermal growth factor receptor 2 (HER2) and immune checkpoints, offer the potential for curative outcomes, challenging this treatment paradigm. CASE DESCRIPTION: This case series presents four UMGC patients treated at Loma Linda University and City of Hope who achieved either pathologic complete response (pCR) or sustained responses following neoadjuvant chemotherapy incorporating dual blockade with anti-HER2 monoclonal antibodies and immune checkpoint inhibitors (ICIs). Initially deemed ineligible for curative resection due to disease extent, these patients demonstrated remarkable responses to biomarker-driven systemic therapy. Restaging imaging showed significant tumor regression, allowing for successful surgical resection. Histopathological findings confirmed treatment response, reinforcing the role of targeted therapies in downstaging disease and improving outcomes. CONCLUSIONS: These cases highlight the transformative impact of biomarker-driven therapy in advanced GC. The integration of programmed cell death ligand 1 (PD-L1) inhibitors and HER2-targeted agents alongside chemotherapy can enable curative-intent surgery in select patients who otherwise would have remained ineligible. These findings emphasize the importance of early biomarker testing to guide individualized treatment plans, ensuring optimal therapeutic benefit. Further studies are needed to refine patient selection criteria, optimize treatment sequencing, and establish standardized protocols integrating biomarker-driven approaches into the management of advanced GC.