KRAS Mutations Linked to Immunotherapy Resistance in Gastric Adenocarcinoma Research Finds

KRAS alterations occur in approximately 10% of gastric adenocarcinomas and define a distinct molecular subset of the disease. They act as potent oncogenic drivers, yet how oncogenic KRAS shapes the immune microenvironment of gastric tumours and drives resistance to immunotherapy has remained poorly understood.

In a new study published in Science China Life Sciences, researchers first performed whole exome sequencing on tumour specimens from patients with gastric adenocarcinoma who had received neoadjuvant chemotherapy combined with PD 1 blockade. Among recurrently mutated genes associated with poor treatment outcomes, KRAS stood out.

Patients with KRAS mutant tumours derived very limited benefit even when their tumours were classified as dMMR with a CPS score above 10, two established biomarkers predicting response to immune checkpoint inhibitors. Multiplex immunohistochemistry confirmed that these tumours were poorly infiltrated by lymphocytes, most strikingly through a depletion of intratumoural CD8+ T cells, together with increased infiltration of CD68+ myeloid cells.

To investigate the underlying biology, the team generated a stomach specific, genetically faithful and immunocompetent mouse model of KRASG12D driven gastric adenocarcinoma, known as the CPPK model. It is based on Anxa10-CreERT2, KrasG12D, and Trp53 floxed alleles and was developed alongside matched organoids and cell lines.

The model recapitulates the development of human poorly differentiated gastric adenocarcinoma, from early antralisation of gastric glands to advanced tubular and intestinal type adenocarcinoma, followed by liver and peritoneal metastasis. Consistent with the clinical observations, CPPK mice were intrinsically resistant to PD 1 blockade.

Single cell RNA sequencing of tumour tissues uncovered a profoundly immunosuppressive microenvironment. Regulatory T cells (Tregs) comprised 41.7% of tumour T cells, while 55.3% of the NKT compartment consisted of exhausted T cells. TGF beta signalling was markedly activated in tumour Tregs, where it showed spatial co localisation with the CTLA 4 molecule. These findings point to Tregs positive for TGF beta as a key cellular hub sustaining immune suppression.

Treatment with MRTX1133, a recently developed inhibitor of KRASG12D, effectively suppressed tumour growth and prolonged survival in the mouse model. It also inhibited KRASG12D gastric cancer cell lines and organoids, with IC50 values of 271 to 485 nM.

However, functional immune analyses revealed that effective antitumour immunity was not restored. Immune cells expanding after KRAS inhibition were predominantly immunosuppressive Tregs, while cytotoxic T cell activity remained unchanged. Mechanistically, TGF beta signalling was required to maintain Treg dominance and suppress effector T cell activity.

Building on these insights, the researchers combined KRAS inhibition with CTLA 4 blockade, a strategy that directly targets Tregs. The treatment markedly attenuated TGF beta activity, impaired Treg function, and synergistically enhanced antitumour immune responses. Adding PD 1 blockade on top of this doublet led to complete eradication of three subcutaneous tumours and significantly prolonged survival in the spontaneous CPPK model.

The findings identify oncogenic KRAS as a key regulator of TGF beta dependent immune suppression and provide a strong preclinical rationale for CTLA 4 based combination immunotherapy in this molecularly defined subset of patients.

The study was carried out by researchers from Peking University Cancer Hospital and Institute and collaborating institutions, with support from grants from the National Science and Technology Major Project of China, the Beijing Natural Science Foundation, and the National Natural Science Foundation of China.