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KRASG12D inhibition reprograms the tumor-induced immunosuppressive environment and enhances NK cell-mediated

Tuo Hu1,2,3, Taiwei Mo2,4, Lin Wang1

  • 1Department of General Surgery (Gastric Surgery, Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510507, China.

Science Advances
|July 23, 2026
PubMed

Insights

KRASG12D inhibition with MRTX1133 combats cancer by reducing immunosuppressive cells and enhancing natural killer (NK) and T cell activity. This combination therapy shows synergistic antitumor effects and improves survival in KRASG12D-mutant cancers.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • KRASG12D mutations are key drivers in pancreatic and colorectal cancers, promoting tumor growth and immune suppression.
  • The tumor microenvironment in these cancers is characterized by myeloid-derived suppressor cells (MDSCs) and suppressed immune cell function.

Purpose of the Study:

  • To investigate the immunomodulatory effects of KRASG12D inhibition using MRTX1133.
  • To evaluate the synergy between KRASG12D inhibition and natural killer (NK) cell-based immunotherapies.

Main Methods:

  • Treatment of cancer models with MRTX1133, a KRASG12D inhibitor.
  • Analysis of immune cell populations (MDSCs, NK cells, CD8+ T cells) and immune signaling pathways.
  • Assessment of combination therapy efficacy with IL-15 or adoptive NK cell transfer.

Main Results:

  • MRTX1133 reduced MDSC accumulation and promoted NK and CD8+ T cell infiltration and activation.
  • KRASG12D inhibition reversed systemic immunosuppression and improved the fitness of adoptively transferred NK cells.
  • MRTX1133 stabilized IFNGR1 by reducing palmitoylation, enhancing IFN-γ signaling and up-regulating NK cell-activating ligands (ICAM1, ULBP1).

Conclusions:

  • KRASG12D inhibition with MRTX1133 remodels the tumor immune microenvironment, sensitizing cancer cells to NK cell-mediated killing.
  • Combining MRTX1133 with NK cell therapies or IL-15 demonstrates synergistic antitumor activity and prolonged survival.
  • These findings provide a strong mechanistic basis for using KRASG12D inhibitors in combination with NK cell immunotherapies for KRASG12D-mutant cancers.

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