Duality of KRAS/STK11 co-mutation subtype in lung cancer：immunological paradox and therapeutic opportunities

doi:10.3760/cma.j.cn371439-20251128-00099

Abstract

Abstract:

The co-mutation of KRAS and STK11 （also known as LKB1） defines a distinct molecular subtype （KL subtype） in lung cancer，which is characterized by an "immunological paradox" — the coexistence of a high tumor mutation burden and primary resistance to immune checkpoint inhibitors. This resistance of this subtype mainly stems from the immunosuppressive microenvironment established by multiple mechanisms，including aberrant recruitment of myeloid cells，metabolic reprogramming，and synergistic interactions with the KEAP1/NRF2 pathway. Current therapeutic strategies for the KL subtype have shifted toward multi-pronged combination interventions，such as directly targeting KRAS^G12C，modulating the immune microenvironment，and exploring emerging therapies. Although clinical translation still faces challenges including model limitations，tumor heterogeneity，and combination-related toxicities，the integration of multi-omics analysis，innovative trial design，and novel therapeutic modalities holds promise for transforming the KL subtype from a treatment-refractory entity into a tractable therapeutic target. These advances collectively provide a theoretical foundation and clear direction for future therapeutic development targeting this specific subtype.

Key words: Lung neoplasms, Genes, ras, Tumor microenvironment, Immunotherapy, STK11 gene

Gao Mi, Gan Kui, Zhu Jun, Huang Meijin. Duality of KRAS/STK11 co-mutation subtype in lung cancer：immunological paradox and therapeutic opportunities[J]. Journal of International Oncology, 2026, 53(10): 628-634.

Figures/Tables 2

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