Distinct molecular subtypes of KRASG12C-mutant lung adenocarcinoma: Insights into clinical outcomes, tumour microenvironments and therapeutic strategies.

Background KRASG12C is the most common KRAS mutation in lung adenocarcinoma (LUAD), yet clinical responses to KRASG12C-selective inhibitors (G12Ci) and immunotherapy remain variable.Methods Transcriptomic analysis of KRASG12C-mutant LUAD was performed using machine learning algorithms to classify molecular subtypes. Subtype-specific features, including genomic alterations, tumour microenvironment and therapeutic vulnerabilities, were systematically evaluated.Results We identified three distinct molecular subtypes (KC1, KC2 and KC3) of KRASG12C-mutant LUAD through transcriptomic analysis using machine learning algorithms. KC1 subtype is characterised by a neuroendocrine phenotype associated with SMARCA4 loss-of-function and frequent STK11 co-mutations, with a relatively good prognosis. It exhibits poor immune infiltration and demonstrates resistance to G12Ci and immunotherapy but shows sensitivity to MEK1/2 inhibitors; KC2 subtype exhibits a highly malignant phenotype with high proliferation, increased glucose metabolism, and the poorest prognosis. It is enriched with T-cell infiltration and responds best to G12Ci monotherapy and immunotherapy. KC3 subtype is distinguished by well differentiation and the best survival, with an immune-enriched microenvironment featuring abundant immune-suppressive cancer-associated fibroblasts. It demonstrates limited sensitivity to G12Ci and a moderate response to immunotherapy. Notably, KC1‒3 subtype-specific molecular signatures predict drug sensitivity more accurately than classical KRASG12C signalling models.Conclusions These findings illuminate the intricate interplay between tumour subtypes, microenvironmental factors and therapeutic responses, offering a robust framework for improved patient stratification and the development of personalised therapeutic strategies KRASG12C-mutant LUAD.Key Points Three novel molecular subtypes (KC1, KC2 and KC3) of KRASG12C-mutant lung adenocarcinoma were identified, each with distinct molecular and clinical characteristics. These subtypes demonstrate differential responses to both KRASG12C targeted therapy and immunotherapy, influencing treatment outcomes. This new classification system enables biomarker-guided combination therapies and informs future clinical trial design for these cancers.