Background <p>Poorly differentiated gastric adenocarcinoma with squamous differentiation is a rare and aggressive malignancy, with limited representation in the literature. Its biological behaviour remains poorly characterized, and prognosis is generally poor. Here, we present a case that highlights the role of biomarker-driven, non-surgical management in advanced gastric malignancy, particularly in the context of high PD-L1 expression in an elderly patient.</p> Case presentation <p>A 75-year-old Syrian Arab male presented with anaemia, weight loss and anorexia. Imaging revealed a large ulcerated gastric mass measuring 9 × 11 cm with perigastric lymphadenopathy and local invasion, but no evidence of distant metastasis. Histopathological examination confirmed poorly differentiated adenocarcinoma with squamous differentiation. Immunohistochemistry demonstrated diffuse p40 positivity and focal cytokeratin 7 (CK7) positivity. Notably, programmed death-ligand 1 (PD-L1) expression was strongly positive, with a combined positive score (CPS) of 75. The patient was started on combined chemotherapy (oxaliplatin and 5-fluorouracil) and immunotherapy (nivolumab). Remarkably, follow-up positron emission tomography–computed tomography (PET-CT) at 3 months showed a reduction in tumour size and metabolic activity, with near complete radiological remission by 6 months. At 1-year follow-up, the patient remains clinically well and disease-free without surgical intervention.</p> Conclusions <p>This case illustrates how high PD-L1 expression may substantially alter the expected clinical course of gastric cancer, even in rare and poorly differentiated subtypes typically associated with poor outcomes. The observed durable clinical complete response underscores the potential of biomarker-guided chemo-immunotherapy and supports consideration of non-surgical approaches in selected patients.</p>