Eliciting DNA damage in tumor cells continues to be one of the most successful strategies against cancer. This is the case for classical chemotherapy drugs and radiotherapy. In the modern era of personalized medicine, this strategy tries to identify specific vulnerabilities found in each patient’s tumor, to inflict DNA damage in certain cell contexts that end up in massive cancer cell death. Cells rely on multiple DNA repair pathways to fix DNA damage, but cancer cells frequently exhibit defects in these pathways, many times being tolerant to the damage. Key vulnerabilities, such as BRCA1/BRCA2 mutations, have been exploited with PARP inhibitors, leveraging synthetic lethality to selectively kill tumor cells and improving patients’ survival. In the DNA damage response (DDR) network, kinases ATM, ATR, Chk1, and Chk2 coordinate DNA repair, cell cycle arrest, and apoptosis. Inhibiting these proteins enhances tumor sensitivity to DNA-damaging therapies, especially in DDR-deficient cancers. Several small-molecule inhibitors targeting ATM/Chk2 or ATR/Chk1 are currently being tested in preclinical and/or clinical settings, showing promise in cancer models and patients. Additionally, pharmacological blockade of ATM/Chk2 and ATR/Chk1 axes enhances the effects of immunotherapy by increasing tumor immunogenicity, promoting T-cell infiltration and activating immune responses. Combining ATM/Chk2- or ATR/Chk1-targeting drugs with conventional chemotherapy, radiotherapy or immune checkpoint inhibitors offers a compelling strategy to improve treatment efficacy, overcome resistance, and enhance patients’ survival in modern oncology.

Eliciting DNA damage in tumor cells continues to be one of the most successful strategies against cancer. This is the case for classical chemotherapy drugs and radiotherapy. In the modern era of personalized medicine, this strategy tries to identify specific vulnerabilities identified in each patient’s tumor, to inflict DNA damage in certain cell contexts that end up in massive cancer cell death. Cells rely on multiple DNA repair pathways to fix DNA damage, but cancer cells frequently exhibit defects in these pathways, many times being tolerant to the damage. Key vulnerabilities, such as BRCA1/BRCA2 mutations, have been exploited with PARP inhibitors, leveraging synthetic lethality to selectively kill tumor cells and improving patients’ survival. In the DNA damage response (DDR) network, kinases ATM, ATR, Chk1, and Chk2 coordinate DNA repair, cell cycle arrest, and apoptosis. Inhibiting these proteins enhances tumor sensitivity to DNA-damaging therapies, especially in DDR-deficient cancers. Several small-molecule inhibitors targeting ATM/Chk2 and ATR/Chk1 are currently being tested in preclinical and/or clinical settings, showing promise in cancer models and patients. Additionally, pharmacological blockade of ATM/Chk2 and ATR/Chk1 axes enhances the effects of immunotherapy by increasing tumor immunogenicity, promoting T-cell infiltration and activating immune responses. Combining ATM/Chk2- or ATR/Chk1-targeting drugs with conventional chemotherapy, radiotherapy or immune checkpoint inhibitors offers a compelling strategy to improve treatment efficacy, overcome resistance, and enhance patients’ survival in modern oncology.

Background/Objectives: Non-small cell lung cancer (NSCLC) comprises biologically heterogeneous tumors, primarily lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), which differ in genomic landscape and clinical behavior. The tumor suppressor PTEN is a key negative regulator of the PI3K/AKT/mTOR pathway and is frequently inactivated in NSCLC through genetic and non-genetic mechanisms. Although reduced PTEN expression has been associated with poor outcomes in lung cancer, its prognostic relevance across these histological subtypes remains unclear. Methods: Here, we investigated the prognostic significance of PTEN in NSCLC subtypes using a multi-level approach combining protein, transcriptomic, and genomic analyses. PTEN protein expression was evaluated by immunohistochemistry in a tissue microarray from resected NSCLC patients, and findings were validated using publicly available datasets including TCGA-RPPA, GEO/EGA-based transcriptomic cohorts, and large genomic resources. In parallel, mutational landscapes and co-mutation patterns were analyzed in several independent datasets, and tumor immune microenvironment composition was inferred using CIBERSORT deconvolution analysis. Results: Low PTEN protein and mRNA levels, as well as PTEN mutations, were consistently associated with significantly worse overall survival (OS) in LUAD but not in LUSC. Multivariable Cox regression analysis confirmed PTEN as an independent prognostic factor in LUAD. Although PTEN mutations were more frequent in LUSC, they showed no prognostic value in this subtype. Co-mutation analyses revealed recurrent PTEN partnerships with TP53, EGFR, and APC in LUAD, with PTEN-TP53 co-alterations enriched in metastatic disease. Immune deconvolution demonstrated that PTEN-low LUAD tumors were characterized by an immunosuppressive microenvironment, including increased T regulatory cells and reduced inflammatory immune populations. Notably, increased M2-like macrophages were associated with shorter OS in PTEN-low LUADs, whereas a high number of total macrophages (CD68+ cells) emerged as an independent predictor of more favorable OS. Conclusions: Collectively, these results identify PTEN loss as a subtype-specific prognostic biomarker in LUAD and link its deficiency to immunosuppressive tumor microenvironment remodeling.