TP53 CpG Site Mutations Predict the Survival of First‐Line Chemoimmunotherapy in Advanced Lung Adenocarcinoma

Background Chemoimmunotherapy is the first‐line standard for advanced lung adenocarcinoma (LUAD) without driver mutations, but predictive biomarkers are still limited. TP53 is the most frequently mutated gene in LUAD, and its mutation subtypes affect treatment efficacy differently. Methods This is a retrospective observational study. We retrospectively analyzed 133 patients with advanced LUAD who received first‐line chemoimmunotherapy in our hospital. TP53 mutations were classified using a multidimensional approach. Key subtypes were identified through elastic‐net and multivariate Cox regression analyses in clinical cohorts. The underlying mechanisms were further explored by transcriptomic and pathway analyses, including gene set variation analysis (GSVA) and immune cell deconvolution, using TCGA data. Results An elastic‐net Cox model within the TP53‐mutant cohort identified three key features: TP53 variant allele frequency (VAF), CpG site mutation status, and dominant‐negative effects (DNE)–loss‐of‐function (LOF) classification. Subsequent multivariate Cox regression in the full cohort confirmed that TP53 mutations at CpG sites were an independent favorable prognostic factor. Patients harboring CpG site mutations had significantly longer median progression‐free survival (PFS) for first‐line chemoimmunotherapy than both non‐CpG‐mutant and wild‐type patients. Exploratory transcriptomic analyses revealed that CpG‐mutant tumors were associated with an immune‐activated tumor microenvironment (TME) characterized by enhanced T‐Cell receptor (TCR) signaling, antigen presentation, IFN‐γ signaling, and CD8 + T‐cell infiltration, whereas non‐CpG‐mutant tumors exhibited a glycolytic metabolic profile and potentially reduced immune activity. Conclusions In conclusion, this study demonstrates that TP53 mutations at CpG sites define a distinct subgroup of patients with advanced LUAD who derive significantly greater PFS benefit from first‐line chemoimmunotherapy.