ABSTRACT Long‐chain polyunsaturated fatty acids (LCPUFAs) modulate therapeutic efficacy of various tumors. Omega‐3 LCPUFAs were reported to synergize with radiotherapy on non‐small cell lung cancer (NSCLC). However, the specific components and functional mechanisms of LCPUFA oxidative metabolites remain to be investigated. This study aimed to validate the relationship of LCPUFAs and their oxylipins with NSCLC radiosensitivity and to clarify the underlying mechanisms of their impacts. Liquid chromatography‐tandem mass spectrometry was used to assess the plasma concentrations of LCPUFA and their oxylipins in 39 adults with NSCLC and 44 healthy controls (HCs). Higher ω‐3 LCPUFA plasma levels were measured in the radiosensitive versus radioresistant adults with NSCLC (OR: 2.34, 95% CI [1.42, 3.86], p < 0.001; OR: 0.28, 95% CI [0.15, 0.51], p < 0.001), while 16 differential oxylipins were screened out (VIP > 1, p < 0.05 and FC > 1.5 or < 0.667). After cross analysis with the 33 LCPUFA metabolites differentially measured between the NSCLC and HC groups, five lipoxygenase products from ω‐3 LCPUFAs significantly different in the adults with NSCLC were higher in the radiosensitive group. These oxylipins reduced NSCLC cell viability in a dose‐dependent manner, and among them 16‐hydroxydocosahexaenoic acid (HDHA) substantially promoted NSCLC cell radiosensitivity. Further research indicated that 16‐HDHA enhanced irradiation‐induced DNA damage and apoptosis and inhibited NSCLC cell proliferation and migration through peroxisome proliferator‐activated receptor (PPAR) γ signaling pathway.

INTRODUCTION:Third-generation EGFR- tyrosine kinase inhibitors (TKIs) are the standard first-line therapy for EGFR-mutant advanced NSCLC. Prospective data on toxicity-driven switching to alternative third-generation TKIs for intolerant patients remain limited. METHODS:In this prospective, multicenter, single-arm phase II trial (NCT04882345), patients with EGFR-mutant advanced NSCLC who developed grade 2 or higher hematologic toxicities or increase in alanine transaminase (ALT) or aspartate transaminase (AST), or grade 3 or higher nonhematologic adverse events (AEs) (excluding ALT or AST increase) on osimertinib received aumolertinib 110 mg once daily after AEs recovered to grade 1 or lower. The primary end point was the 3-month conversion success rate (absence of disease progression, grade ≥2 hematologic AEs or increase in ALT or AST, and grade ≥3 nonhematologic AEs). RESULTS:Of the 40 enrolled patients, 39 received aumolertinib, and 34 were evaluable for the primary end point. The 3-month conversion success rate was 70.6% (95% confidence interval: 52.5-84.9) in the evaluable population, with 78.9% in nonhematologic toxicity and 60.0% in hematologic toxicity subgroups. Median postswitch progression-free survival was 11.6 months, and the 3-year postswitch overall survival rate was 52.4%. Treatment-related AEs occurred in 69.2% of patients (grade ≥3: 15.4%), with no aumolertinib discontinuation or death. CONCLUSIONS:This prospective trial suggests that switching to aumolertinib achieves sustained efficacy and manageable safety in osimertinib-intolerant EGFR-mutant advanced NSCLC, supporting toxicity-driven EGFR-TKI switching as a feasible clinical strategy.

BACKGROUND:Radioresistance is fundamental to glioma progression and poor prognosis. Understanding its underlying mechanisms and identifying novel therapeutic targets through elucidating key molecules in glioma radiosensitivity pathways are therefore of significant clinical importance. METHODS:Radiosensitivity-related genes were identified based on radiotherapy response, glioma stemness, and prognosis. A predictive signature was constructed using Lasso-Cox regression and validated via clinicopathological, functional enrichment, immune infiltration, and correlation analyses. GPX8 expression and prognostic significance were assessed by tissue microarray. In vitro functional and radiobiological assays, complemented by in vivo subcutaneous xenograft models using BALB/c nude mice (treated with or without radiotherapy), evaluated the role of GPX8 in regulating malignant progression and radiosensitivity in glioma. RESULTS:The radiosensitivity-related signature demonstrated significant potential in predicting glioma malignancy and prognosis, serving as an indicator of the mesenchymal subtype and contributing to the maintenance of an immunosuppressive microenvironment. GPX8 was overexpressed in high-grade gliomas and correlated with recurrence and poor survival. Knockdown of GPX8 suppressed the malignant biological behaviors of glioma cells. Radiation upregulated GPX8 expression while GPX8 knockdown significantly enhanced the cytotoxicity of radiation and induced apoptosis by promoting oxidative stress and DNA damage. Suppression of GPX8 effectively potentiated radiosensitivity in murine xenograft models and reduced intratumoral infiltration of tumor-associated macrophages. CONCLUSIONS:The radiosensitivity-related signature serves as a significant predictor for assessing glioma malignancy and prognosis. GPX8 acts as a key regulator of malignant phenotypes and radiosensitivity in glioma, positioning it as a promising therapeutic target to counteract both malignant progression and radioresistance.

Precise spatial distribution of interstitial needles is critical for 3D-printing-assisted brachytherapy in cervical cancer. This study proposes a greedy algorithm-based needle trajectory planning (GANTP) framework to generate patient-specific needle configurations while ensuring needle collision avoidance and achieving clinically acceptable high-risk clinical target volume (HR-CTV) coverage in compliance with OAR dose constraints. The GANTP framework comprises three core steps: (1) Generation of candidate trajectories anchored within clinically viable entry zones; (2) Parameter-driven greedy selection of needle trajectories based on a geometric influence radius (δ) evaluated at three discrete values (12, 15, and 18 mm), where δ serves as a geometric surrogate for dose coverage, together with a geometric coverage-ratio threshold (γ = 98

Introduction Obesity is closely associated with the risk of cancers. This study analyzed national population surveys from the United States and China to investigate the association between weight-adjusted waist index (WWI) and thoracic cancer. Material and methods Data from two national population surveys were used in the study. Logistic regression analysis was used to analyze the association between WWI and thoracic cancer. Restricted cubic spline (RCS) analysis was used to investigate a potential nonlinear relationship. The stability of this relationship across different subgroups was assessed through subgroup analysis. ROC curve analysis facilitated the evaluation of different obesity indicators in terms of their efficacy in predicting thoracic cancer. Results A relationship between thoracic cancer and WWI was identified. RCS analysis confirmed the nonlinear relationship between thoracic cancer and WWI (p for nonlinear < 0.001). The analysis of subgroups indicated that the association between thoracic cancer and WWI was broadly applicable across different populations, further confirming the robustness of the study findings. ROC analysis showed that WWI possessed satisfactory predictive capability for thoracic cancer. Conclusions The study showed that WWI was independently associated with thoracic cancer prevalence in both the United States and Chinese populations. Furthermore, the accuracy of WWI in predicting thoracic cancer risk surpasses that of conventional obesity indicators.

3596 Background: KRAS G12C mutation is a key driver in approximately 3-4% of colorectal cancer (CRC) cases with poor prognosis. Sosimerasib is a novel, potent, and highly selective KRAS G12C inhibitor. This Phase 1b study evaluates the efficacy and safety of sosimerasib in patients with KRAS G12C-mutated locally advanced or metastatic CRC. Methods: Eligible patients who had received prior standard chemotherapy were enrolled in this study. Patients were administered sosimerasib at 500 mg orally once daily. The primary efficacy endpoint was the objective response rate (ORR) assessed by investigators according to RECIST 1.1. Results: As of May 3, 2025, a total of 56 patients were enrolled with a median age of 59 years (53.6% male). All patients had stage IV disease at baseline with an ECOG score of 0 (19.6%) or 1 (80.4%). Prior treatment lines ranged from 1 to 3, and most patients (38; 67.9%) had received oxaliplatin, irinotecan, and fluoropyrimidine as systemic therapy during the advanced disease period. With a median follow-up period of 9.9 months (range: 2.1-13.4), the confirmed ORR was 39.3% (95% CI: 26.5-53.3), the median time to response was 1.4 months (range: 1.3-4.2), and the disease control rate was 98.2% (95% CI: 90.5-100). The median duration of response was 8.6 months (95% CI: 4.2-NA). The median progression-free survival was 8.3 months (95% CI: 5.6-11.0). The median overall survival (OS) was not reached, with a 12-month OS rate of 71.5%. Among the patients who had previously received oxaliplatin, irinotecan, and fluoropyrimidine in the advanced setting, the confirmed ORR was 31.6% (95% CI: 17.5-48.7). Treatment-related adverse events (TRAEs) were reported in 53 (94.6%) patients, with grade 3-4 TRAEs occurring in 14 (25.0%) patients. No TRAE was fatal. The most common TRAEs were increased alanine aminotransferase (48.2%), increased aspartate aminotransferase (46.4%), anaemia (32.1%), and decreased white blood cell count (26.8%). TRAEs led to drug interruption in 9 (16.1%) patients, dose reduction in 3 (5.4%) patients, and permanent discontinuation in 1 (1.8%) patient. Conclusions: Sosimerasib monotherapy demonstrated clinically meaningful anti-tumor activity with an acceptable safety profile in patients with KRAS G12C-mutated locally advanced/metastatic CRC, supporting its potential for further development. Clinical trial information: ChiCTR2200059986.

Background:The efficacy of immunochemotherapy (ICT) remains poor in patients with polymetastases from esophageal squamous cell carcinoma (ESCC). While radiation therapy (RT) has shown promise in oligometastatic settings, its role when combined with ICT for polymetastatic ESCC (with >5 metastatic lesions) remains unclear. Objective:This study evaluated the efficacy and value of RT in patients with polymetastatic ESCC who received ICT as first-line treatment. Design:This multi-center cohort study was conducted at 20 hospitals in China. Methods:In total, 331 patients who received at least one cycle of first-line ICT between January 2019 and December 2021 were enrolled. Among them, 88 received ICT plus RT (RT group), and 243 received ICT alone (non-RT group). Propensity score matching (PSM) was performed to control for potential confounders (75 patients/group). Outcomes included overall survival (OS), progression-free survival, objective response rate (ORR), symptom control, and safety. This study was registered at the Clinicaltrials.gov registry (identification number NCT05142709). Results:Both before and after PSM, no significant OS benefit was observed with RT group (median OS: 15.2 vs 12.2 months, hazard ratio (HR) 0.80 (0.60-1.07), p = 0.14; 15.0 vs 11.0 months, HR 0.80 (0.55-1.15), p = 0.23, respectively), though pre-PSM ORR favored RT (59.1% vs 40.3%, p = 0.003). RT demonstrated superior symptom control, with significantly higher rates of dysphagia improvement (63.3% vs 36.4%, p = 0.0006) and meaningful pain reduction (59.4% vs 40.0%, p = 0.007). Grade ⩾3 treatment-related adverse events were comparable between groups (38 vs 40 cases post-PSM, p = 0.74), with equivalent grade 5 toxicities (1.3% each). Conclusion:For polymetastatic ESCC, RT combined with ICT enhanced symptom control without severe toxicity, though it did not improve survival. This supports its personalized use for quality of life in symptomatic patients.

Mature red blood cells (RBCs), the most abundant anucleate cells in humans, have long been overlooked as DNA carriers. Recent evidence implicates RBC-derived DNA (rbcDNA) as a potential biomarker for cancer diagnostics, yet its origin and how RBCs acquire tumor DNA remain poorly understood. Here, we find that mature RBCs harbor short DNA fragments distinct from genomic DNA. Both in vivo and in vitro experiments confirm that RBCs can internalize extracellular DNA and reflect tumor burden. Oxford Nanopore sequencing of rbcDNA reveals that short rbcDNA fragments are homologous to extracellular cell-free DNA (cfDNA). We identify apoptotic bodies (apoBDs) as key mediators of extracellular DNA uptake by RBCs, triggering RBC deformation, Heinz body formation, oxidative stress, and vesiculation. Tumor apoBD-treated RBCs are rapidly cleared in vivo via a partly macrophage-dependent effect, causing local immunosuppression in the spleen. Clinically, rbcDNA shows no advantage in detecting driver mutations compared with cfDNA, but its abundance significantly correlates with tumor burden and treatment response. Overall, our findings offer novel insights into RBC biology and support rbcDNA's clinical application in liquid biopsy.

8514 Background: PD-1/ PD-L1 inhibitors plus platinum-based chemotherapy is the standard first-line therapy for locally advanced or metastatic sq-NSCLC. Improvements in clinical benefits of sq-NSCLC receiving antiangiogenic agents and immune-checkpoint inhibitors have remained elusive, highlighting an urgent need to develop new therapeutic strategies. TQB2450-III-12 is a multicenter, randomized, double-blind, parallel-controlled phase III study of benmelstobart (PD-L1 inhibitor) in combination with chemotherapy followed by sequential combination with anlotinib (multi-targeted angiogenesis inhibitor) versus tislelizumab plus chemotherapy as first-line therapy for locally advanced or metastatic sq-NSCLC. Methods: Patients with unresectable locally advanced or metastatic sq-NSCLC without prior systematic therapy were randomized 1:1 to receive benmelstobart (1200 mg, Q3W) plus chemotherapy for 4 cycles followed with benmelstobart plus anlotinib (10mg, P.O., D1-D14, Q3W) (group A) or tislelizumab (200mg, Q3W) plus chemotherapy for 4 cycles followed with tislelizumab (group B). Paclitaxel (175 mg/m 2 , day 1) and carboplatin (area under the concentration [AUC] of 5, day 1) were given every 3 weeks. The primary endpoint was PFS per RECIST 1.1 by independent review committee and the key secondary endpoint was OS. Here we present the primary interim analysis for PFS per prespecified analysis plan. Results: As of March 1, 2024, 565 patients were randomized 1:1 to group A and group B. Baseline characteristics were well balanced. Median PFS was significantly improved in group A (10.12 months, 95% CI, 8.54–NE) versus group B (7.79 months, 95% CI, 6.87–9.69), HR=0.64 (98.35% CI, 0.45–0.93; P =0.0038). The subgroup analysis showed that PFS benefit favored group A in almost all subgroups, particularly in patients with ECOG PS 0 (HR 0.44, 0.23-0.84), PD-L1 expression (tumor proportion scoring) of 1-49% (HR 0.47, 0.30-0.73), and age <65 years (HR 0.59, 0.39-0.90). The ORR of group A and group B were 71.9% and 65.1%, respectively. The median DoR was longer in group A (9.69 months, 95% CI, 8.44, NE) than Group B (8.34 months; 95% CI, 5.78-NE) HR=0.58 (95% CI, 0.38, 0.88; P=0.0091). OS was immature. ≥Grade 3 benmelstobart/tislelizumab or anlotinib/ placebo-related adverse events was 61.57% in group A and 51.06% in group B. There was no difference of the grade 5 treatment-emergent adverse events (TEAE) between the treatment groups (group A: 5.69%, group B: 5.63%). The discontinuation of any treatment components by TEAE was 4.27% in group A and 5.28% in group B. Conclusions: Benmelstobart in combination with chemotherapy followed by sequential combination with anlotinib significantly improved PFS, with a manageable safety profile. It might be a new first-line treatment for sq-NSCLC. Clinical trial information: NCT05718167 .

PURPOSE:Preclinical studies showed that low-dose radiation therapy (LDRT) may act synergistically with immunotherapy in small cell lung cancer (SCLC); however, its role in the treatment of extensive-stage SCLC (ES-SCLC) remains unclear. METHODS AND MATERIALS:This single-arm, multicenter, Simon's 2-stage, phase 2 study enrolled treatment-naïve patients with ES-SCLC. Patients received 4 21-day cycles of intravenous cisplatin (75 mg/m2) or carboplatin (area under the curve value, 5 mg/mL/min), etoposide (100 mg/m2), and atezolizumab (1200 mg), with concurrent LDRT (15 Gy in 5 fractions [3 Gy/fraction]), followed by atezolizumab maintenance therapy until loss of clinical benefit, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was the confirmed objective response rate. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS:Fifty-six eligible patients were enrolled between December 16, 2020, and March 30, 2022. The median follow-up was 36.1 months (IQR, 30.9-38.7) at the cutoff date (June 30, 2024). The confirmed objective response rate was 87.5% (95% CI, 75.9-94.8). The median PFS and OS were 6.9 months (95% CI, 5.4-9.3) and 16.9 months (95% CI, 14.0-32.9), respectively. The PFS rates at 1 and 3 years were 27.3% and 20.7%, respectively, and the OS rates at 1 and 3 years were 69.6% and 35.1%. The median depth of tumor response among patients with confirmed objective response was 70.2%. The 3-year OS rates were 57.4% and 18.8% in patients above and below the median depth of tumor response, respectively (hazard ratio, 0.28; 95% CI, 0.13-0.60). The most common treatment-related grades 3 to 5 adverse events were decreased neutrophil count (60.7%) and decreased white blood cell count (58.9%). CONCLUSIONS:These findings suggest that upfront LDRT concurrent with atezolizumab plus chemotherapy was effective and tolerable as first-line treatment for ES-SCLC, warranting further verification in randomized controlled trials.

3133 Background: Natural killer (NK) cells play a crucial role in tumor progression and anti-tumor immunity. However, they often exhibit an exhausted phenotype within the tumor microenvironment (TME), limiting their full cytotoxic potential. T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) has emerged as a novel immune checkpoint that is highly expressed on NK cells and suppresses their cytotoxic function. TIM-3 is closely associated with immune evasion and anti-tumor immune tolerance. This study aims to investigate the effects and mechanisms by which radiation modulates NK cell function, providing a foundation for developing strategies that specifically target TIM-3 on NK cells. Methods: First, mRNA high-throughput sequencing, RT-qPCR, and Western blot experiments were used to analyze changes in the expression of related genes in NK92 cells after radiotherapy. The LDH release assay was employed to evaluate the effect of radiation on the viability of NK92 cells. ELISA was conducted to detect changes in the release levels of tumor necrosis factor TNF-α and other factors after radiotherapy. Dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP) experiments confirmed that the transcription factor MYB mediates radiation-induced regulation of NK cell activation by targeting and binding to the TIM-3 promoter region. A non-contact co-culture system was established, and flow cytometry demonstrated that radiation combined with MYB overexpression enhanced the cytotoxicity of NK cells against tumor cells. A colon cancer mouse model was constructed to evaluate the anti-tumor effect of combining anti-TIM-3 antibodies with radiotherapy. Results: We found that radiation can activate NK92 cells in vitro and enhance TIM-3 expression,promoting the secretion of granzyme B, perforin, TNF-α, IFN-γ, and other cytokines and chemokines that modulate the TME and enhance anti-tumor immune responses. Moreover, the transcription factor MYB inhibits TIM-3 expression by directly binding to the TIM-3 promoter region, mediating the effects of radiation on the TME through NK cell activation. In vivo, the combination of radiotherapy and anti-TIM-3 antibodies effectively controlled the growth of subcutaneously transplanted colon cancer tumors in C57BL/6 mice. However, this combined treatment effect was significantly diminished after NK cells were depleted by the anti-NK1.1 antibody. Conclusions: This study elucidates a novel mechanism by which radiation activates NK cells in the tumor microenvironment through the MYB/TIM-3 pathway. It provides new insights for enhancing the efficacy of radiotherapy and offers a theoretical basis for the potential clinical application of these cells in future research.

BACKGROUND:Trophoblast cell-surface antigen 2 (Trop2), a transmembrane glycoprotein overexpressed in multiple cancers, plays crucial roles in tumor progression and therapy resistance, yet its expression patterns and clinical significance in digestive cancers remain incompletely characterized. METHODS:This retrospective study analyzed a consecutive cohort of 2370 patients with histologically confirmed digestive cancers (804 gastric [GC], 1,384 colorectal [CRC], and 182 pancreatic cancers [PC]). Comprehensive clinicopathological data were systematically collected. Trop2 expression was quantitatively evaluated by immunohistochemistry and classified into Trop2-negative, Trop2-low, and Trop2-high based on the product of staining intensity and the proportion of positive tumor cells. Statistical analyses included univariate and multivariate logistic regression were used to identify significant clinicopathological and molecular predictors of Trop2 expression patterns. Univariate and multivariate logistic regression analyses were used to explore the relationship between Trop2 expression status (positive [Trop2 intensity ≥ 2] vs. negative) and various clinicopathological features of different tumor types. RESULTS:Trop2 was widely expressed in digestive cancers, with highest prevalence in PC and GC. Multivariate analysis revealed distinct Trop2 expression patterns in gastrointestinal malignancies. At the pan-cancer level, Trop2 expression significantly correlated with tumor type, (signet ring cell carcinoma) SRCC, vascular invasion (VI) and perineural invasion. Notably, GC showed independent associations with SRCC and intestinal-type Lauren classification; CRC showed VI as the predominant factor associated with Trop2 expression; while PC demonstrated unique correlations with female sex and T1 stage. These findings highlight tumor-type specific regulation of Trop2, providing critical insights for prognostic assessment and targeted therapy. CONCLUSION:Trop2 is a promising biomarker for tumor aggressiveness and a potential target for antibody-drug conjugates (ADCs) in digestive cancers, particularly in SRCC-rich, metastatic, and invasive subtypes. These findings provide strong rationale for stratifying patient populations in future clinical investigations of Trop2-directed ADC therapies.

Non-small cell lung cancer (NSCLC) patients may exhibit tumor marker expression patterns that do not align with their pathological subtype, yet the clinical significance of these mismatches remains unclear. This study aims to identify novel tumor marker expression patterns and explore their relationship with tumor heterogeneity and progression-free survival (PFS) in NSCLC patients. Clinical data and serum tumor marker values were collected from 142 patients with stage III–V, unresectable NSCLC in the Zhongnan Hospital of Wuhan University. The Self-organizing map algorithm was used to generate novel tumor marker patterns. We analyzed the association of these patterns with clinicopathological features and prognosis. The in vitro experiment was conducted to evaluate the impact of CA125 on the malignant behavior of squamous cell carcinoma cell lines. We identified a pattern of low expression of SCC and high expression of CA125 in squamous cell carcinoma patients (HR 2.1704, P = 0.0304), as well as low expression of CEA and high expression of SCC in adenocarcinoma patients (HR 2.3771, P = 0.0235). Both patterns were significant predictors of poor prognosis. Furthermore, squamous cell carcinoma cell lines cultured in a high-CA125 environment exhibited accelerated proliferation in vitro. NSCLC patients with a pattern of tumor markers mismatched to their pathological type had unfavourable PFS, suggesting a potentially higher degree of tumor heterogeneity.

The CD47/SIRPα axis conveys a 'don't eat me' signal, thereby thwarting the phagocytic clearance of tumor cells. Although blocking antibodies targeting CD47 have demonstrated promising anti-tumor effects in preclinical models, clinical trials involving human cancer patients have not yielded ideal results. Exploring the regulatory mechanisms of CD47 is imperative for devising more efficacious combinational therapies. Here, we report that inhibiting USP2 prompts CD47 degradation and reshapes the tumor microenvironment (TME), thereby enhancing anti-PD-1 immunotherapy. Mechanistically, USP2 interacts with CD47, stabilizing it through deubiquitination. USP2 inhibition destabilizes CD47, thereby boosting macrophage phagocytosis. Single-cell RNA sequencing shows USP2 inhibition reprograms TME, evidenced by increasing M1 macrophages and CD8+ T cells while reducing M2 macrophages. Combining ML364 with anti-PD-1 reduces tumor burden in mouse models. Clinically, low USP2 expression predicts a better response to anti-PD-1 treatment. Our findings uncover the regulatory mechanism of CD47 by USP2 and targeting this axis boosts anti-tumor immunity.

Objective To investigate the clinical efficacy and prognosis of cross-line immunotherapy for driver gene-negative advanced non-small cell lung cancer(NSCLC).Methods Clinical data of patients with advanced NSCLC in Zhongnan Hospital of Wuhan University from June 2019 to December 2023 were retrospectively analyzed.For first-line treatment for the patients,programmed cell death receptor-1(PD-1)monoclonal antibody combined with platinum-based doublet chemotherapy was adopted,and for second-line treatment,PD-1 monoclonal antibody combined with chemotherapy was used.The Kaplan-Meier method was employed to draw survival curves,and the Log-rank test was used to evaluate the differences in survival.The Cox proportional hazards regression model was used to analyze the risk factors that affect prognosis and subgroup analyses were conducted to explore the impact on patients'prognosis.Results A total of 112 advanced NSCLC patients with negative driver genes were included.The overall response rate(ORR)of cross-line immunotherapy was 20.54％,and the disease control rate(DCR)of cross-line immunotherapy reached 49.11％.The median overall survival(OS)was 26.6 months.The median progression free survival of first-line treatment(PFS-1)was 7.3 months,and that of second-line treatment(PFS-2)was 5.4 months.The subgroup analysis showed that,compared with patients with PFS-1≤10 months,patients with PFS-1＞10 months had longer median OS[44.3 months vs.13.8 months,P＜0.001]and median PFS-2[10.0 months vs.3.5 months,P＜0.01].Patients with BMI＞25 kg/m2 had longer median PFS-2 than those with BMI≤25 kg/m2[10.0 months vs.4.2 months,P＜0.05].Moreover,in contrast to patients with low expression of PD-L1(＜1％PD-L1 on tumor cells or tissues),patients with high expression of PD-L1 had a longer median PFS-2[6.9 months vs.2.5 months,P＜0.01].In the multivariate Cox proportional hazards regression analysis,compared with patients with PFS-1≤10 months,patients with PFS-1＞10 months had a 52％reduction in the risk of progression[HR=0.48,95％CI(0.27,0.87),P＜0.05].Conclusion The benefits of cross-line immunotherapy might not be remarkable for advanced non-small cell lung cancer with negative driver genes.However,patients with PFS-1＞10 months may have a better prognosis.

Radiation-induced lung injury (RILI) limits radiotherapy dose for thoracic tumors. It is currently urgent to clarify RILI pathogenesis and find safe and effective therapeutical strategy. Transcriptomics of RILI mouse lungs indicate that cellular senescence is substantially involved in RILI pathogenesis, and anti-senescence compounds alleviate RILI and pulmonary inflammatory. Single-cell RNA sequencing and multi-color immunofluorescence demonstrate that type II alveolar epithelial cells (AECIIs) are the main senescent cells, and quantitative proteomics illustrate that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is more secreted. Clinical samples also confirms that the plasma levels of TRAIL are significantly increased in RILI patients. Mechanistically, AECII-specific TRAIL knockout (Trailf/f;Sftpc-Cre) mice presents reduced cellular senescence and RILI, accompanied by reduced mitophagy. Soluble TRAIL activates the mTOR pathway through death receptor 5 to hinder mitophagy, resulting in impaired mitochondrial accumulation and cellular senescence. Immunoprecipitation mass spectrometry identifies that endoplasmic reticulum (ER)-localized transmembrane molecule TMEM131 interact with TRAIL and mediates its transportation from ER to Golgi through Sec23 homolog A of the coat protein complex II. Interruption of this transportation process led to ER-associated degradation of TRAIL proteins through ubiquitylation. The results indicate the pro-senescent role of TRAIL during RILI pathogenesis and reveals the TMEM131-mediated intricate secretory process of TRAIL.

Lung cancer is one of the most lethal tumors worldwide, of which non-small cell lung cancer (NSCLC) accounts for 80-90% of cases. For patients with locally advanced but surgically unresectable NSCLC, radiotherapy is the fundamental treatment. With the extensive research on nanomaterials, they have been investigated as drug delivery platforms or radio-sensitizing reagents in the treatment of NSCLC. We successfully synthesized the nanoparticles encapsulated cisplatin (CDDP) and iron ions (Fe3+) in the zeolitic imidazolate framework (ZIF)-8 nanosystem as CDDP@Fe/ZIF-8 (CFZ), and explored their effects on the radiosensitivity of NSCLC. In vitro cellular assays demonstrated that CFZ combined with radiation synthetically inhibited NSCLC cell proliferation, promoted oxidative stress and apoptosis, and induced cell cycle arrest. The results of tumor-bearing mouse model experiments suggested that CFZ safely and effectively strengthened the radiosensitivity of NSCLC cells in vivo. Our research indicated the good biosafety and high drug loading capacity of ZIF-8 nanocarriers as a drug delivery system, and that the CFZ nanosystem safely improved the radiosensitivity of NSCLC. Further validation and modification of ZIF-8 nanocarriers as radio-sensitizing metal elements may be a promising direction for the improvement of radiotherapy efficacy in NSCLC.