Search Results (317)

The landscape of first-line treatment for metastatic non-small cell lung cancer (NSCLC) without actionable driver mutations is rapidly evolving, currently dominated by pembrolizumab-based regimens. This review discusses the unique molecular characteristics of cemiplimab, a newer anti-PD-1 antibody, and defines its optimal positioning against established standards. Cemiplimab is a fully human IgG4 monoclonal antibody distinguished by two key features: an engineered hinge-region mutation that prevents Fab-arm exchange, ensuring exceptional molecular stability which minimizes anti-drug antibody (ADA) risks associated with unstable molecules; and a unique interaction with PD-1 glycosylation sites, potentially enhancing binding efficacy. These structural advantages may be particularly relevant in histologies like squamous NSCLC, where accumulating somatic mutations drive high neoantigen loads and heightened immune responses, creating an environment historically prone to ADA formation. Based on data from the pivotal EMPOWER-Lung program, we highlight cemiplimab’s exceptional promise in specific populations. Firstly, in the EMPOWER-Lung 1 trial, cemiplimab monotherapy demonstrated extraordinary survival benefits in a pre-specified analysis of the distinct “ultra-high” PD-L1 expression subgroup (TPS ≥90%), potentially surpassing historical benchmarks. Secondly, cemiplimab displays consistent, robust efficacy in challenging-to-treat squamous histology, both as monotherapy for patients with high PD-L1 expression and in combination with chemotherapy for patients with PD-L1 < 50%. In conclusion, cemiplimab establishes a unique therapeutic niche for patients with squamous histology and ultra-high PD-L1 expression, likely driven by its distinct structural stability and reduced immunogenicity. Full article

Background and Objectives: Lung cancer in never-smokers (LCINS) has become a major global health concern, ranking as the fifth leading cause of cancer-related mortality. Unlike smoking-related lung cancer, LCINS arises from complex interactions between environmental carcinogens and distinct genomic alterations. This review summarizes current evidence on environmental risks, molecular features, and therapeutic progress shaping lung cancer management. Methods: A narrative review was conducted to examine risk factors for lung cancer in non-smokers. Studies reporting driver mutations in never-smokers and smokers were identified across major lung cancer histological subtypes, including small-cell lung cancer (SCLC), lung adenocarcinoma (LUAD), squamous cell carcinoma (SCC), and large-cell carcinoma (LCC). In addition, PubMed was searched for phase III trials and studies on targeted therapies related to driver mutations published between 2016 and 2025. Results: Environmental factors such as cooking oil fumes, radon, asbestos, arsenic, and fine particulate matter (PM_2.5) are strongly associated with LCINS through oxidative stress, DNA damage, and chronic inflammation. EGFR, PIK3CA, OS9, MET, and STK11 mutations are characteristic of never-smokers, in contrast to TP53 mutations, which are more common in smokers. Recent advances in targeted therapy and immunotherapy have improved survival and quality of life, emphasizing the importance of molecular profiling for treatment selection. Conclusions: LCINS represents a distinct clinical and molecular entity shaped by complex interactions between environmental exposures and genetic susceptibility. Genetic alterations promote tumor immune evasion, facilitating cancer development and progression. Continued advances in air quality control, molecular diagnostics, and precision therapies are essential for prevention, early detection, and reduction of the global disease burden. Full article

Background: Advances in molecular pathology have transformed NSCLC (Non-Small Cell Lung Cancer) diagnosis, prognosis, and treatment by enabling precise tumor characterization and targeted therapeutic strategies. We review key genomic alterations in NSCLC, including EGFR (epidermal growth factor receptor) mutations, ALK (anaplastic lymphoma kinase) and ROS1 (ROS proto-oncogene 1) rearrangements, BRAF (B-Raf proto-oncogene serine/threonine kinase) mutations, MET (mesenchymal–epithelial transition factor) alterations, KRAS (Kirsten rat sarcoma) mutations, HER2 (human epidermal growth factor receptor 2) alterations and emerging NTRK (neurotrophic receptor tyrosine kinase) fusions and AXL-related pathways. Methods: A total of 48 patients with NSCLC was analyzed, including 22 women and 26 men (mean age 70 years, range 44–86). Tumor specimens were classified histologically as adenocarcinomas (n = 81%) or squamous cell carcinomas (n = 19%). Smoking history, PD-L1 (programmed death-ligand 1) expression, and genetic alterations were assessed. NGS (Next-generation sequencing) identified genomic variants, which were classified according to ACMG (American College of Medical Genetics and Genomics) guidelines. Results: The cohort consisted of 29 former smokers, 13 current smokers, and 5 non-smokers (12%), with a mean smoking burden of 33 pack years. PD-L1 TPS (tumor proportion score) was ≥50% in 10 patients, ≥1–<50% in 22, and <1% in 15 patients. In total, 120 genomic variants were detected (allele frequency ≥ 5%). Of these, 52 (43%) were classified as likely pathogenic or pathogenic, 48 (40%) as variants of unknown significance, and 20 (17%) as benign or likely benign. The most frequently altered genes were TP53 (tumor protein p53) (31%), KRAS and EGFR (15% each), and STK11 (serine/threonine kinase 11) (12%). Adenocarcinomas accounted for 89% of all alterations, with TP53 (21%) and KRAS (15%) being most common, while squamous cell carcinomas predominantly harbored TP53 (38%) and MET (15%) mutations. In patients with PD-L1 TPS ≥ 50%, KRAS mutations were enriched (50%), particularly KRAS G12C and G12D, with frequent co-occurrence of TP53 mutations (20%). No pathogenic EGFR mutations were detected in this subgroup. Conclusions: Comprehensive genomic profiling in NSCLC revealed a high prevalence of clinically relevant mutations, with TP53, KRAS and EGFR as the dominant drivers. The strong association of KRAS mutations with high PD-L1 expression, irrespective of smoking history, highlights the interplay between genetic and immunological pathways in NSCLC. These findings support the routine implementation of broad molecular testing to guide precision oncology approaches in both adenocarcinoma and squamous cell carcinoma patients. Full article

The mesenchymal–epithelial transition (MET) receptor is a tyrosine kinase activated by its sole known ligand, hepatocyte growth factor (HGF). MET signaling regulates key cellular processes, including proliferation, survival, migration, motility, and angiogenesis. Dysregulation and hyperactivation of this pathway are implicated in multiple malignancies, including lung, breast, colorectal, and gastrointestinal cancers. In non–small cell lung cancer (NSCLC), aberrant activation of the MET proto-oncogene contributes to 1% of known oncogenic drivers and is associated with poor clinical outcomes. Several mechanisms can induce MET hyperactivation, including MET gene amplification, transcriptional upregulation of MET or HGF, MET fusion genes, and MET exon 14 skipping mutations. Furthermore, MET pathway activation represents a frequent mechanism of acquired resistance to EGFR- and ALK-targeted tyrosine kinase inhibitors (TKIs) in EGFR- and ALK-driven NSCLCs. Although MET has long been recognized as a promising therapeutic target in NSCLC, the clinical efficacy of MET-targeted therapies has historically lagged behind that of EGFR and ALK inhibitors. Encouragingly, several MET TKIs such as capmatinib, tepotinib, and savolitinib have been approved for the treatment of MET exon 14 skipping mutations. They have also demonstrated potential in overcoming MET-driven resistance to EGFR TKIs or ALK TKIs. On 14 May 2025, the U.S. Food and Drug Administration granted accelerated approval to telisotuzumab vedotin-tllv for adult patients with locally advanced or metastatic non-squamous NSCLC whose tumors exhibit high c-Met protein overexpression and who have already received prior systemic therapy. In this review, we summarize the structure and physiological role of the MET receptor, the molecular mechanisms underlying aberrant MET activation, its contribution to acquired resistance against targeted therapies, and emerging strategies for effectively targeting MET alterations in NSCLC. Full article

Background: Durvalumab consolidation following radiochemotherapy is now the standard treatment for unresectable stage III non-small cell lung cancer (NSCLC). [¹⁸F]FDG PET/CT offers valuable insights not just for staging but also for tumor characterization via radiomics, which can potentially predict histology, immunophenotype, and prognosis. Methods: We conducted a retrospective analysis of [¹⁸F]FDG PET/CT scans from stage IIIA–IIIB NSCLC patients treated at the Clinical Centre, University of Pécs. All biopsy samples were classified histologically (squamous vs. adenocarcinoma) and tested for PD-L1. Lung tumors were segmented using MEDISO InterViewTM FUSION software (version 3.12.002.0000). with an SUVmax threshold of four. Imaging features were extracted and compared based on histology, PD-L1 status, and neutrophil-to-lymphocyte ratio (NLR)-based prognosis groups. Statistical analyses were performed with Jamovi (v2.6.44), using Shapiro–Wilk, t-test/ANOVA, Mann–Whitney/Kruskal–Wallis, or Chi-square tests as appropriate. Results: Fifty-six patients were included (38 PD-L1-positive, 18 -negative). Among PD-L1-positive cases, poor versus good NLR prognosis groups differed in maximum diameter (p = 0.046), short-zone emphasis (p = 0.026), and zone-length non-uniformity (p = 0.027). Focusing on PD-L1-positive squamous carcinoma, maximum diameter, metabolic tumor volume, busyness, and coarseness showed significant differences (all p < 0.05). SUVmax, mean SUV, SUVpeak, and complexity were higher in squamous than in adenocarcinoma subtypes. PD-L1-positive and -negative squamous tumors differed in zone percentage (p = 0.039) and long-zone high gray-level emphasis (p = 0.024), while no significant differences were observed among adenocarcinomas. Conclusions: [¹⁸F]FDG PET/CT radiomics showed potential for differentiating NSCLC histological subtypes and for identifying PD-L1-associated imaging patterns in squamous cell carcinoma. In addition, certain metabolic features were associated with NLR-based prognostic groups in PD-L1-positive patients. Full article

Lineage plasticity, the ability of cancer cells to alter their differentiated state through transcriptional and epigenetic reprogramming, has emerged as a key mechanism of therapeutic resistance across cancers. This adaptive process can manifest in multiple ways, including epithelial–mesenchymal transition, acquisition of stem-like features, and histological transformation, the most striking and clinically apparent example. In EGFR-mutant lung adenocarcinoma (LUAD), lineage plasticity is increasingly recognized as a prevalent mechanism of acquired resistance to tyrosine kinase inhibitors (TKIs). Among its visible manifestations, histologic transformation into small-cell lung cancer (SCLC) is the most frequent, while squamous transformation and other phenotypic shifts also occur. Transformed tumors typically retain the initiating EGFR mutation but lose EGFR dependence, acquire neuroendocrine features, and display aggressive clinical behavior with poor clinical outcomes compared with both de novo SCLC and non-transformed LUAD. Recent studies show that plasticity arises through combined genomic, transcriptomic, and epigenetic reprogramming, often foreshadowed by molecular alterations before overt histological change. Spatial and single-cell profiling reveal heterogeneous trajectories and intermediate states, while functional models and multi-omics approaches have begun to identify therapeutic vulnerabilities distinct from both de novo EGFR-mutated SCLC and classical EGFR-mutated LUAD. Thus, lineage plasticity, whether manifested as histologic transformation or through more subtle epigenetic reprogramming, represents a formidable resistance mechanism in NSCLC. Defining its molecular basis and temporal dynamics will be essential for early detection, prognostication, and the development of tailored therapies. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Among the NSCLC subtypes, squamous cell carcinoma (SCC) is less frequently associated with actionable genetic alterations. Herein, we present the first known case of ROS1 rearrangement in pure SCC, identified using next-generation sequencing (NGS), and successfully treated with entrectinib for approximately one year. This case highlights the potential of ROS1 as a therapeutic target in SCC, which has historically been considered rare, as ROS1-rearranged SCC accounts for only 0.2% according to the Foundation Medicine database. This underscores the importance of incorporating NGS into clinical practice, particularly for never smokers/light smokers or patients with advanced SCC of the lungs, to identify targetable mutations and guide personalized therapy. Full article

Background: Lung cancer (LC) is a complex-to-treat disease and remains the leading cause of cancer-related mortality. Methods: Our aim was to investigate the prognostic role of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio (MLR) in patients with LC. In this retrospective study, examining the period between 1 June 2020 and 31 May 2024, we recorded consecutive patients who presented to the Department of Respiratory Medicine, University Hospital of Patras, Patras, Greece, and received a first diagnosis of LC. The primary outcome was mortality risk analysis based on NLR, PLR, and MLR at diagnosis. Secondary outcomes included associations of tumor, node, metastasis (TNM) staging, and smoking with NLR, PLR, and MLR at diagnosis. Results: We identified 353 patients with a first diagnosis of LC. The mean age ± SD at the time of diagnosis was 68.1 ± 9.1 years. Most patients were male (77.9%, n = 275) and current or ex-smokers (58.1%, n = 205, and 39.1%, n = 138, respectively). Histological diagnosis was non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC), and not otherwise specified (NOS) in 67.1% (n = 237), 29.8% (n = 105), and 3.1% (n = 11) of patients, respectively. Adenocarcinoma NSCLC was more common (40.2%, n = 142) compared to squamous NSCLC (25.5%, n = 90). In 12.9% of patients, we identified EGFR, KRAS, ALK, or BRAF molecular driver mutations, while PD-L1 expression was positive in 20.7% of patients. The majority of enrolled patients presented with advanced stage IV LC at diagnosis (63.2%, n = 223). Kaplan–Meier curves showed that patients with higher than the median NLR and PLR at diagnosis were associated with significantly higher mortality risk compared to those with lower than the median [HR: 0.58, (95% CI: 0.42 to 0.81) p = 0.0009 and HR: 0.71, (95% CI: 0.53 to 0.95) p = 0.02, respectively], while no differences in mortality risk were observed between patients with higher versus lower than the median MLR [HR: 0.84, (95% CI: 0.63 to 1.12) p = 0.22]. With regard to secondary outcomes, no associations between higher versus lower than the median NLR, PLR, or MLR values and TNM staging [4.0 (95% CI: 4.0–4.0) vs. 4.0 (95% CI: 4.0–4.0), p = 0.95, 4.0 (95% CI: 4.0–4.0) vs. 4.0 (95% CI: 4.0–4.0), p = 0.09, 4.0 (95% CI: 4.0–4.0) vs. 4.0 (95% CI: 4.0–4.0), p = 0.4, respectively], as well as smoking status [70 (95% CI: 60–80) vs. 80 (95% CI: 60–80), p = 0.10, 70 (95% CI: 60–80) vs. 80 (95% CI: 60–80), p = 0.46, 80 (95% CI: 60–80) vs. 70 (95% CI: 60–80), p = 0.96, respectively] were reported. Conclusions: NLR and PLR could serve as reliable and clinician-friendly prognosticators of clinical outcomes in patients with LC. Further validation cohorts are sorely needed to prove this notion. Full article

Background/Objectives: Genomic profiling guides treatment in metastatic non-small-cell lung cancer (mNSCLC), yet country-level data from Türkiye remain limited. Methods: We retrospectively analyzed consecutive patients with mNSCLC diagnosed between January 2018 and March 2025 across tertiary centers in all seven regions. Variables included demographics, smoking, histology, testing modality (single-gene vs. next-generation sequencing [NGS]), targetable genomic alterations (TGAs) and co-mutations, and programmed death-ligand 1 (PD-L1) tumor proportion score. Results: Among 1023 patients (mean age 64 years; 76.4% male), tobacco exposure was frequent (mean 42.1 pack-years); 16.9% were never-smokers. NGS use increased over time, exceeding 90% by 2025. TGAs were detected in 28.3% (EGFR 16.0%, ALK 5.0%, KRAS G12C 2.6%, BRAF V600E 3.2%; ROS1, MET exon 14, HER2, NTRK ≤ 2.5%; no RET). EGFR alterations occurred in 19% of non-squamous carcinomas and 6% of squamous cell carcinomas (SCCs), suggesting an intermediate East–West pattern. Among NGS-tested samples, TP53 was the most frequent co-mutation (33.1%), followed by alterations in CDKN2A, PIK3CA, FGFR, STK11, and KEAP1. Conclusions: In this large, multicenter Turkish real-world cohort, the TGA spectrum broadly mirrors global patterns while revealing local nuances; EGFR mutations were more frequent than expected in SCC, and nationwide NGS adoption is accelerating. Limitations include retrospective design, non-centralized PD-L1 testing, and missing data. Prospective, standardized studies integrating outcomes and resistance mechanisms are warranted to refine regional precision oncology. Full article

SOX (SRY-related HMG-box) transcription factors are key regulators of embryogenesis and vascular development, with emerging roles in cancer biology. In non-small-cell lung cancer (NSCLC), the contributions of SOX18 and SOX30 remain insufficiently understood, particularly regarding their epigenetic regulation and network interactions with angiogenic and immune-modulatory pathways. We examined 800 NSCLC specimens (400 lung adenocarcinomas, 400 squamous cell carcinomas) using immunohistochemistry, RT-qPCR, Western blotting, and spatial transcriptomics to profile SOX18, SOX30, and related signaling partners (SOX7, SOX17, MEF2C—Myocyte Enhancer Factor 2C, VCAM1—Vascular Cell Adhesion Molecule 1, p-STAT3—Signal Transducer and Activator of Transcription 3). Epigenetic regulation was assessed via droplet digital methylation-specific PCR of promoter CpG islands, while functional validation employed adenoviral delivery of hsa-miR-24-3p in NSCLC cell lines and 3D spheroid cultures. SOX18 protein was markedly overexpressed in both NSCLC subtypes, despite reduced transcript levels and consistent promoter hypermethylation, suggesting post-transcriptional regulation. In contrast, SOX30 expression was uniformly downregulated at both mRNA and protein levels, frequently linked to promoter hypermethylation, especially in squamous carcinoma. Spatial transcriptomics revealed SOX18 enrichment at tumor cores and invasive borders, co-localizing with MEF2C, VCAM1, and p-STAT3 in vascular and stromal niches, while SOX30 expression remained low across all tumor regions. Functional assays demonstrated that hsa-miR-24-3p suppressed SOX18 expression and partially modulated SOX30 and MEF2C, reinforcing a miRNA-driven regulatory axis. In summary, SOX18 and SOX30 play divergent roles in NSCLC progression: SOX18 functions as a pro-oncogenic factor driving angiogenesis and tumor–stroma interactions, while SOX30 acts as an epigenetically silenced tumor suppressor. Regulation of SOX18 by miR-24-3p highlights a potential therapeutic vulnerability. These findings underscore the significance of SOX transcription factors as biomarkers and potential targets for novel treatment strategies in NSCLC. Full article

Lung cancer remains the most prevalent and deadliest malignancy worldwide. According to the European Society for Medical Oncology guidelines for non-oncogene-addicted metastatic non-small-cell lung cancer (NSCLC), patients with metastatic squamous-cell carcinoma (LUSC) or metastatic non-squamous NSCLC with performance status 2 and PD-L1 < 50% may receive single-agent chemotherapy with gemcitabine (GEM), docetaxel (DOC), or vinorelbine. Herein, we investigated the cellular effects of GEM/DOC as monotherapies in NSCLC cell lines—lung adenocarcinoma, A549 and CALU6; LUSC, H520 and H1703. Treatment with GEM/DOC may induce apoptotic cell death in all NSCLC cell lines at 48 h. GEM/DOC can affect cancer cell migration assessed by scratch assay. Both GEM/DOC may produce distinct effects on cell cycle arrest, consistent with their particular pharmacodynamic effects. Furthermore, GEM/DOC induced signals consistent with autophagic activity in LUSC cell lines, but only GEM triggered signals consistent with autophagic activity in the CALU6 cell line. Analysis of three key long non-coding RNAs (lncRNAs)—MALAT1, NEAT1, and HOTAIR—showed variable expression in the studied cell lines as a potential response to DOC and GEM treatment. Our findings indicate different cellular effects of GEM and DOC in NSCLC cell lines and provide an overview of how currently used chemotherapeutics may influence the expression of lncRNAs. Full article

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and show notable success in some cancer types such as non-small cell lung cancer, melanoma and colorectal cancers, while they demonstrate relatively low response rate in others, such as esophageal cancers. Due to the heterogeneous nature of the tumor microenvironment and patient-to-patient variability, there remains a need to improve ICI response rates. Combining ICIs with therapies that can overcome resistance is a promising strategy. Compared to de novo drug development, drug repurposing offers a faster and more cost-effective approach to identifying such combination candidates. A variety of computational drug repurposing tools leverage genomics and/or transcriptomic data. As single-cell RNA sequencing (scRNA-seq) technology becomes available, it enables precise targeting of cancer-driving cellular components. In this review, we highlight current computational drug repurposing tools utilizing scRNA-seq data and demonstrate the application of two such tools, scDrug and scDrugPrio, on an esophageal squamous cell carcinoma dataset to identify potential drug candidates for combination with ICI therapy to enhance treatment response. scDrug focuses on predicting tumor cell-specific cytotoxicity, while scDrugPrio prioritizes drugs by reversing gene signatures associated with ICI non-responsiveness across diverse tumor microenvironment cell types. Together, this review underscores the importance of a multi-faceted approach in computational drug repurposing and highlights its potential for identifying drugs that enhance ICI treatment. Future work can expand the application of these strategies to multi-omics and spatial transcriptomics datasets, as well as personalized patient samples, to further refine drug repurposing involving ICI therapy. Full article

Circulating cell-free DNA (cfDNA) sequencing offers a minimally invasive approach for profiling tumor genomes, but detecting copy number alterations (CNAs) from cfDNA whole-exome sequencing (WES) remains technically challenging due to noise and guanine–cytosine (GC)-related bias. Building upon our previous study that characterized read count patterns in cfDNA WES data, we developed and evaluated an advanced pipeline for robust CNA detection in patients with advanced non-small cell lung cancer (NSCLC). Read count signals showed strong correlation with GC content, and applying locally estimated scatterplot smoothing (LOESS)-based GC bias correction effectively reduced false positives and improved CNA detection. The resulting cfDNA CNA profiles were reproducible within patients and showed strong concordance with The Cancer Genome Atlas (TCGA) tissue-level patterns for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). These findings demonstrate that cfDNA WES, when combined with appropriate bias correction, can serve as a practical and minimally invasive alternative for genomic characterization of NSCLC. Full article

Background: Non-small-cell lung cancer (NSCLC) is often diagnosed at stage IV, when prognosis depends on metastatic spread. The impact of histopathology on the first metastatic site remains underexplored. Methods: We retrospectively analyzed 364 patients with stage IV NSCLC diagnosed at OncoHelp Medical Center, Timișoara, Romania (2020–2024). All underwent baseline CT chest–abdomen–pelvis, whole-body FDG PET-CT, and brain MRI within seven days of histological confirmation. Patients were stratified into adenocarcinoma (n = 164), squamous cell carcinoma (n = 112), and large-cell carcinoma (n = 88). The first metastatic site was defined as the earliest confirmed location. Associations were evaluated using Fisher’s exact test and multinomial logistic regression. Results: Histology was associated with the first metastatic site (global p = 0.013). Adenocarcinoma was more likely than squamous carcinoma to present with brain metastases (RRR 3.74, 95% CI 1.48–9.45; p = 0.005; p_FDR = 0.053) and showed directional signals toward bone and adrenal involvement. Squamous carcinoma more frequently spread to the pleura as the first site (adjusted p = 0.008). Large-cell carcinoma showed no consistent differences compared to squamous carcinoma. In adenocarcinoma subgroups, EGFR-mutant tumors most often metastasized to the brain (55.6%), KRAS-mutant tumors to the liver (44.4%), and ALK-rearranged tumors to bone (100%). Conclusions: The first metastatic site in NSCLC follows histology-specific patterns, with adenocarcinoma favoring hematogenous spread and squamous carcinoma showing locoregional involvement. Molecular status further refines these patterns in adenocarcinoma. Incorporating histology into baseline staging may improve diagnostic efficiency and prognostic accuracy. Full article

Immune checkpoint inhibitors (ICIs) and thoracic radiotherapy are standard treatments for advanced non-small-cell lung cancer (NSCLC), especially in patients with high PD-L1 expression or symptoms such as superior vena cava syndrome (SVCS). Both therapies carry a risk of pulmonary toxicity, which may be exacerbated by opportunistic infections due to corticosteroid use. We report a unique case of a 65-year-old man with squamous-cell NSCLC and high PD-L1 expression (80%), who developed a rare complication: radiation recall pneumonitis (RRP), with superimposed Pneumocystis jirovecii pneumonia and severe symptomatic hyponatremia induced by trimethoprim/sulfamethoxazole (TMP-SMX). The coexistence of these three complications—radiotherapy- and immunotherapy-associated lung injury, opportunistic infection, and electrolyte imbalance—represents an exceptional clinical scenario not previously described in the literature. This report highlights the importance of differential diagnosis, early recognition of complications, and close monitoring of electrolytes in NSCLC patients undergoing complex treatment regimens. Full article