Lung cancer remains the leading cause of cancer-related deaths, driven by complex pathogenesis and poor prognosis. Recognizing the pivotal role of mitochondrial RNA modifications (MRM) in cancer progression, this study aims to provide a comprehensive analysis of MRM-related genes and their clinical relevance in lung adenocarcinoma (LUAD). Integrating multi-omic datasets, we systematically explored the molecular features of MRM-related genes across various cancers and identified distinct expression patterns and prognostic associations. Single-cell analysis further reveals MRM-driven cell-cell interactions and pathway activation, particularly in cycling and epithelial cells. Using advanced machine learning techniques, we developed a novel prognostic signature-the Mitochondrial RNA Modification-related Signature (MRMS)-comprising nine genes: TXN, LDHA, HMGA1, SFTPB, KRT8, ALG3, S100A16, HSPD1, and ALDOA. The MRMS demonstrates superior predictive performance for LUAD survival compared to previously reported models. Our findings uniquely link MRMS to increased tumor mutational burden, genetic instability, and an immunosuppressive tumor microenvironment characterized by reduced immune cell infiltration and elevated tumor purity. Additionally, MRMS is associated with immunotherapy-related features, suggesting its potential in predicting treatment response. Experimental validation identified ALG3 as an oncogenic driver in LUAD, influencing tumor cell proliferation, migration, and invasion. In conclusion, this study establishes MRMS as a robust prognostic biomarker and highlights its dual role in shaping the tumor immune microenvironment and guiding therapeutic strategies. These findings provide novel insights into mitochondrial RNA modifications and their potential applications in personalized treatment for LUAD.

Background: Thymic epithelial tumors (TETs), categorized predominantly as thymoma (T) or thymic carcinoma (TC), face a challenging prognosis and limited treatment options. Although chemotherapy remains the established treatment for advanced TETs, its responses tend to be short-lived. The emergence of immunotherapy, particularly programmed cell death-1 (PD-1) and programmed death ligand-1 inhibitors (PD-L1), is increasingly being regarded as a promising new treatment option for various malignancies.Methods: Herein, we present a case series of eight patients with TETs who received tislelizumab treatment at Jiangsu Provincial Hospital between 2021 and 2023. All cases were histologically confirmed as either thymoma or thymic carcinoma. Among these eight cases, six patients (5 thymic carcinomas [TC] and 1 thymoma [T]) received tislelizumab in combination with chemotherapy following multiple cycles of prior chemotherapy without achieving significant therapeutic response. Two TC patients were administered this combination regimen as first-line treatment. Following the initiation of immunotherapy, patients received tislelizumab at a dose of 200 mg every three weeks until disease progression or the occurrence of unacceptable toxicity. Treatment response was assessed by the investigators according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines.Results: The 8 patients described had a median age of 59 years (range, 47-72). During the course of immunotherapy, five patients (62.5%) achieved partial response, and notably, even after transitioning to maintenance therapy with tislelizumab, the lesions continued to shrink, with the longest sustained partial response lasting over 2 years. Three patient (37.5%) experienced stable disease as their best response to immunotherapy. Among all these patients, three patients (37.5%) demonstrated initial efficacy but subsequently exhibited progressive disease (median progression-free survival of 14 months). All patients are still being followed up, with the longest PFS extending to 31 months. Notably, five of the eight patients underwent PD-L1 testing and were all found to be negative. Despite this, no immune-related Grade 3–5 adverse events (AEs) were reported and all AEs were manageable with supportive measures. Grade 1–2 AEs were adrenal insufficiency (n=1), thyroid dysfunction (n=1), and pneumonia (n=1).Conclusions: Our study findings suggest that the combination of immunotherapy and chemotherapy yields durable clinical responses in patients with TETs, suggesting its potential as a safe and effective first-line treatment strategy for advanced TETs. Notably, the therapeutic benefits of chemo-immunotherapy appear to extend beyond patients with high PD-L1 expression (≥50%), indicating that this treatment approach may not be strictly limited to individuals with elevated PD-L1 levels.

Circulating tumour DNA (ctDNA) is a valuable biomarker for relapse monitoring. However, current personalized approaches are unable to detect emerging clones, and perioperative ctDNA dynamics remain to be defined. We prospectively validated Hi-SECURE, a tumour-informed MRD assay, in 132 NSCLC patients (POEM cohort). Analytical performance was benchmarked against reference standards and a fixed 158-gene panel. A perioperative blood (PB) staging system was proposed and externally validated. Hi-SECURE achieves a limit of detection of 0.005% with a DNA input of 20 ng. At the landmark time point, ctDNA positivity predicted recurrence with a hazard ratio (HR) of 17.14 (95% CI: 3.06–96.11). Hi‑SECURE outperformed the fixed panel, especially in stage IA (25.0% vs 6.8% detection rate, p = 0.020). Pre‑ and postoperative ctDNA status enabled PB staging, which showed strong prognostic discrimination (log rank p < 0.001), was validated across external cohorts. Moreover, Hi-SECURE’s core panel identified drug-resistant mutations (e.g., EGFR -T790M) during follow-up, enabling timely therapeutic adjustments. In conclusion, Hi‑SECURE is a highly sensitive and specific personalized MRD assay. The proposed PB staging system provides a functional, dynamic complement to anatomical TNM staging, enabling precise prognostic stratification and offering potential guidance for adjuvant therapy, resistance monitoring, and immunotherapy candidate selection.