Clinical trials combining radiotherapy (RT) with immune checkpoint blockade (ICB) have shown improved outcomes in only a fraction of patients, and optimal strategies for integrating these modalities remain under intense investigation. With a few exceptions, phase III combination trials have yielded disappointing results. This may be due to detrimental effects of RT on the tumor-regional immune microenvironment (TRIME), including tumor-draining lymph nodes (TDLNs) and intratumoral immune aggregates such as tertiary lymphoid structures. TDLNs are crucial for generating tumor-specific T cells, including progenitors of exhausted T cells. Intratumoral immune aggregates are hubs for immune cell interaction participating in induction or reactivation of antitumor immune responses. Understanding the biological role of the TRIME in RT/ICB-induced antitumor immunity is therefore essential for designing RT-immunotherapy combination trials. This review also highlights several potential strategies to optimize RT/ICB combination therapy. One approach involves modifying treatment schedules, for example, delaying RT to TDLNs until after ICB to allow effective immune priming. Another promising strategy is the integration of advanced imaging techniques into RT planning to improve precision and minimize radiation exposure to TDLNs. Applying unconventional RT with lower total dose or to selective areas may help preserve immune aggregates within tumors, potentially enhancing synergy with ICB. Another important approach is the use of dendritic cell agonists to boost the function of the TRIME. These approaches may help unlock the full therapeutic potential of RT/ICB combinations.

BACKGROUND:The precise prognostic stratification of intrahepatic cholangiocarcinoma (iCCA) remains challenging. We aimed to develop and validate interpretable machine learning (ML) models that integrate clinicopathological, metabolic, and immune-inflammatory factors to personalize prognosis prediction. METHODS:We retrospectively collected data from 690 iCCA patients across five centers. Patients from four centers were assigned to training/testing sets (n = 597, 7:3 split), and another single center as an external validation set (n = 93). After feature selection, five survival models were developed and compared for predicting overall survival (OS) and disease-free survival (DFS) using the concordance index (C-index), time-dependent ROC, Kaplan-Meier, calibration and decision curves. SHapley Additive exPlanations (SHAP) interpreted predictions, and a clinically applicable web-based tool was developed. RESULTS:The survival support vector machine (SSVM) model achieved the best predictive performance for both OS and DFS prediction. The SSVM_OS model achieved a C-index of 0.754, and the SSVM_DFS model achieved a C-index of 0.709. Both models showed excellent performance in the external validation set and demonstrated good clinical utility. The models effectively stratified patients into distinct risk groups and outperformed the AJCC-TNM staging system. SHAP analysis identified gamma-glutamyl transferase, triglyceride-glucose index, lymph node metastasis, and carcinoembryonic antigen as the most influential predictors for both OS and DFS. The optimal models were deployed as an online tool to provide individualized risk estimates for death and recurrence, supporting clinical decision-making. CONCLUSIONS:We developed and externally validated explainable ML models to predict postoperative risk for iCCA patients. The best-performed SSVM models were implemented as a clinical decision-support tool to guide personalized surveillance.

Bulky tumors remain challenging to treat, and immune checkpoint inhibitors (ICIs), alone or combined with conventional radiotherapy (RT), yield limited efficacy. We present EclipseRT (ERT), an RT technique that delivers low-dose RT (LDRT) to the gross tumor volume (GTV) and stereotactic body RT (SBRT) to selected subvolume(s) within the GTV. Combined with ICIs (iERT), this approach achieves marked control of bulky tumors through the coordinated activity of NK and CD8⁺ T cells. Single-cell RNA sequencing and validation experiments show that the SBRT component robustly induces type I interferon (IFN-I), which activates NK cells to secrete XCL1, thereby recruiting cross-presenting XCR1⁺ dendritic cells (DCs). SBRT also promotes the release of extracellular vesicles carrying neoantigens, enhancing DC cross-presentation and CD8⁺ T-cell responses. The LDRT component further promotes NK and CD8⁺ T-cell recruitment. iERT also induces precursor exhausted CD8⁺ T cells in tumors and tumor-draining lymph nodes. Collectively, iERT activates the IFN-I/NK/DC/CD8⁺ T-cell axis, driving potent antitumor immunity against bulky tumors.

348 Background: Neoadjuvant chemoimmunotherapy has shown promise in resectable esophageal squamous cell carcinoma (ESCC), yet its efficacy remains limited by relatively low pathologic complete response (pCR) rates. To address this, we proposed reprogramming the tumor immune microenvironment through the addition of low-dose radiotherapy, aiming to synergize with anti-PD-1 immunotherapy without increasing treatment-related toxicity. Methods: This phase II clinical trial was designed to enroll 30 participants. The key inclusion criteria for this study were as follows: Histologically (pathologically) confirmed thoracic esophageal squamous cell carcinoma with clinical stage: cT1b-cT2N1-2M0 or cT3-cT4aN0-2M0. The primary endpoint was pCR rate. During the neoadjuvant therapy phase, patients underwent two cycles of low-dose radiotherapy followed by chemotherapy and immunotherapy, with each cycle lasting 21 days. Patients were allocated into three treatment groups (4Gy/2f, 6Gy/3f, and 8Gy/4f). Tislelizumab, nab-paclitaxel and carboplatin were administered concurrently on the day following radiotherapy completion. Patients were scheduled for esophagectomy 6-8 weeks after the second neoadjuvant session. Blood and tumor tissue samples were collected before and after neoadjuvant therapy. Tumor tissue samples were collected for multi-omics sequencing. Blood samples were analyzed for ctDNA. Results: A total of 30 patients were included for final analysis, with 10 patients in each sub-group (4Gy/2f, 6Gy/3f, and 8Gy/4f) The results demonstrated that the pCR rate in the 8Gy/4f group was 70% (7/10), which was higher than that in the 4Gy/2f group (10%; p = 0.011) and the 6Gy/3f group (50%; p = 0.371). Furthermore, the ctDNA clearance rates in both the 8Gy/4f group (7/10) and the 6Gy/3f group (6/8) were numerically higher than that in the 4Gy/2f group (2/7), with P-values of 0.160 and 0.120, respectively. Among the 30 patients, 23 experienced treatment-related adverse events (TRAEs) of any grade, with the majority being mild (grade 1). Conclusions: The 8Gy/4f radiotherapy followed by chemoimmunotherapy significantly increased the anti-PD-1 immunotherapy efficacy without increasing the treatment-related adverse events or postoperative complications, highlighting promise as an effective neoadjuvant treatment modality. Clinical trial information: ChiCTR2400084438 . Baseline, pathological, and perioperative data of patients. All patients 4Gy/2f 6Gy/3f 8Gy/4f Number of Patients 30 10 10 10 Sex Female 6 2 1 3 Male 24 8 9 7 Age ≥65 14 4 4 6 <60 16 6 6 4 cTNM I 1 0 0 1 II 10 3 5 2 III 10 4 2 4 IV 9 3 3 3 ypTNM I 21 6 8 7 II 1 0 1 0 IIIA 1 0 0 1 IIIB 6 3 1 2 IV 1 1 0 0 pCR Yes 13 1 5 7 No 17 9 5 3 Pre-treatment ctDNA Positive 25 7 8 10 Negative 5 3 2 0 Post-treatment ctDNA Positive 10 5 2 3 Negative 20 5 8 7 Adverse Event (CTCAE) I 12 5 4 3 II 6 1 3 2 III 5 3 0 2 Perioperative Complication (Clavien-Dindo) I 3 1 1 0 II 8 1 5 2 III 1 1 0 0

Abstract Background: We previously showed low-dose radiotherapy (LDRT) exerts immunostimulatory effects in both preclinical models and clinical settings for SCLC, yet its immunogenic cell death (ICD) mechanisms remain unclear. As extracellular vesicles (EVs) mediate intercellular stress signaling, we hypothesized that tumor-derived EVs play a critical role in orchestrating immunogenic signaling in the initial stages of radiotherapy response. This study tracks ICD signals from tumor to DCs via EV monitoring and elucidate their function spectrum throughout this process. Methods: Plasma EVs from prospective extensive-stage-SCLC cohorts treated with LDRT plus chemo-immunotherapy and PDX/PDO-derived EVs post-irradiation underwent proteomic profiling. Post-irradiation cellular components - cell pellets, debris, and EVs - were used to activate DC-T axis respectively. EV inhibition and live-cell imaging confirmed radiation-induced EVs (RT-EVs) activate the axis versus non-irradiated EVs (NT-EVs). SCLC CDX and PDX models were established, and corresponding homogeneous PBMCs were collected for in vivo EV function evaluation.An ICD tracking system based on stable isotope labeling traced EV-mediated immunogenic transfer from irradiated SCLC and MC-38ova cells to DCs. Results: Proteomic analysis identified LDRT-EVs were specifically enriched in DC activation pathways and exhibited stronger ICD hallmarks, termed “Spark-EVs”. Spark-EVs significantly enhanced DC and T cell activation more than other cellular components, with efficacy comparable to whole-cell lysates. Spark-EVs potently activated the DC-T cell axis compared to NT-EVs, whereas the EV release inhibitor reversed this effect to control levels. Live-cell imaging confirmed nearly threefold greater DC uptake of Spark-EVs than NT-EVs (p < 0.0001). In CDX models, Spark-EV-pulsed DCs + anti-PD-1 enhanced tumor suppression versus NT-EVs + anti-PD-1 or anti-PD-1 alone. Patient T cells primed with Spark-EV-pulsed hDCs showed enhanced stemness and cytotoxicity in vitro. Adoptive transfer of these T cells into PDX models yielded superior tumor control. EV-labeled tracing showed that Spark-EVs were enriched with increased OVA antigens, DAMPs (e.g. HSPD1), which deliver into DCs then. Additionally, Integrated multi-level proteomics and prognostic analysis identified Junction plakoglobin (JUP) as a potential key transmitter of ICD signal. Conclusion: Using EV-based tracing, we visualized how LDRT triggers tumor cells to generate Spark-EVs, which deliver enhanced immunogenic signals to DCs. Furthermore, we delineate that radiation-responsive EV-borne proteins (e.g. JUP, HSPD1) that mediate the release, transmission, and effector functions of LDRT-induced immunogenic signaling. These findings establish Spark-EVs as key, targetable messengers of LDRT-driven ICD. Citation Format: Shanghai Liu, Kai Kang, Zhuoran Yao, Ren Luo, Hui Wang, Zichong Peng, Shuangsi Liao, Yilan Zeng, Ruizhan Tong, Jiaming Zeng, Weidi Xiao, Jianxin Xue, Linglu Yi, Chu Wang, You Lu. Tumor-derived extracellular vesicles as key messengers of radiotherapy-induced immunogenic cell death to sensitize small cell lung cancer to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2836.

Small cell lung cancer (SCLC), a highly aggressive neuroendocrine malignancy, exhibits poor response to immunotherapy, and the underlying mechanisms remain unclear. Here, we identify a blood-brain barrier-like vascular gate (BVG) in SCLC, distinct from non-SCLC (NSCLC) and other cancers, composed of tightly connected endothelial cells, a thickened basement membrane, and dense pericyte coverage. Functionally, this blood-brain barrier-like vascular gate restricts immune cell infiltration, contributing to SCLC’s immunotherapy resistance. Mechanistically, achaete-scute family basic-helix-loop-helix (bHLH) transcription factor 1 (ASCL1), the master transcription factor of SCLC, is essential for BVG formation by regulating insulin-like growth factor-binding protein 5 (IGFBP5), which activates the IGF1 signaling in endothelial cells. IGFBP5 knockout or treatment with the IGF1R inhibitor OSI-906 enhances CD8+ T cell infiltration and synergizes with anti-PD1 therapy. Furthermore, this ASCL1-IGFBP5-IGF1R axis and the BVG are conserved across multiple neuroendocrine cancers (NECs). Our findings reveal a previously unrecognized vascular gate in NECs and propose novel therapeutic strategies to enhance immunotherapy efficacy in these recalcitrant cancers.

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy with an immunosuppressive tumor microenvironment, and current immunotherapy provides limited benefit. This highlights the need to identify microenvironmental features enabling effective immune responses. High endothelial venules (HEVs) are critical for lymphocyte recruitment and antitumor immunity, yet their roles in SCLC remain poorly understood. To investigate HEV-related features among SCLC patients, five bulk RNA-seq datasets comprising 583 tumor samples were integrated. HEV-related signatures stratified SCLC patients into two subtypes, C1 and C2, associated with HEV-high and HEV-low states, respectively. C1 showed a more immune-active microenvironment and superior prognosis. Consistently, using single-cell RNA-seq data and validating the findings by immunofluorescence staining in an independent cohort of 80 patients with SCLC, we confirmed that the presence of HEV structures was associated with a favorable prognosis. We further established a prognostic model and identified five genes, PDCD1, CXCL9, ITK, ITGAL, and SH2D1A, as key favorable prognostic factors. A nomogram incorporating age, tumor stage, and the prognostic model was also developed and exhibited satisfactory performance. Additionally, we explored the translational potential of promoting HEV formation as a therapeutic strategy in SCLC. In murine SCLC models, radiotherapy combined with immunotherapy promoted HEV formation and enhanced antitumor efficacy. HEVs appeared to serve as a critical link underlying the therapeutic synergy between radiotherapy and immunotherapy. Collectively, these findings highlight the biological and clinical relevance of HEVs in SCLC and suggest that combination strategies aimed at promoting HEV formation may help overcome the limited efficacy of immunotherapy.

Abstract Background: Small cell lung cancer (SCLC) is a highly aggressive and heterogeneous malignancy, typically classified into four phenotypic subtypes by different transcription factors, referred to as ANYP. Recent studies have highlighted the plasticity between these subtypes, especially neuroendocrine (NE)/ non-NE states, which closely linked to treatment resistance. Emerging evidence suggests that stabilizing the SCLC phenotype could be advantageous for improving clinical outcomes. In this study, we identified a novel RNA-binding protein, ELAVL3, as a key player in the plasticity of SCLC. We discovered that ELAVL3 promotes a more NE-like progression of SCLC by post-transcriptionally disrupting the NOTCH2 signaling pathway. This finding offers new insights into the molecular mechanisms driving SCLC plasticity and proposes potential targets for therapeutic intervention. Methods and Result: Through analysis of single-cell RNA sequencing data from 20 of our SCLC patients and some public databases, ELAVL3 expression is found to be positively correlated with NE signatures in both SCLC cell lines and patient tumors. Transcriptomic analysis and Western blotting results in SCLC cell lines showed that pharmacological inhibition of ELAVL3 with xxx activates NOTCH signaling pathways and induces the loss of NE features, while ELAVL3 overexpression reduces NOTCH2 mRNA levels and helps to maintain the NE characteristics. Some molecular experiments, including RNA immunoprecipitation (RIP)-qPCR, RIP-sequencing and RNA pulldown, further discovered that ELAVL3 extensively binds to and interferes with the RNA stability of NOTCH2 signaling pathway members, thereby enhancing the NE program.Our previous studies have found that immunotherapy (IO) combined with radiotherapy (RT) can be effective for chemotherapy resistant subcutaneous SCLC, which is non-NE type, for a certain period of time. By single-cell RNA sequencing of tumor at multiple time points after IO+RT, we identified a close association among highly expressed ELAVL3, inactivated NOTCH signaling, restored NE characteristics and acquired therapy resistance. After testing various combination therapies in SCLC cell lines, patient-derived organoids, patient-derived tumor xenograft model, and murine SCLC model, we revealed that the inhibition of ELAVL3 hold their differentiation into non-NE types, which better corresponded to the immuno-combination therapies for SCLC after chemotherapy resistance. Conclusions: This study nominates ELAVL3 as a key regulator of the NE state plasticity and defines a novel therapeutic strategy for SCLC. Citation Format: Shuangsi Liao, Zichong Peng, Kai Kang, Shanghai Liu, Hui Wang, Yufeng Zhang, Ren Luo, Linglu Yi, Feifei Na, Guo Lin, Yue Zheng, Jianxin Xue, You Lu, Zhuoran Yao. ELAVL3 post-transcriptionally regulation of the NOTCH2 signaling pathway shapes the plasticity of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5007.

Lung cancer is the leading cause of cancer‑related mortality worldwide. Current therapies continue to face challenges such as drug resistance and tumour heterogeneity. Radionuclide‑drug conjugates (RDCs) represent an emerging theranostic platform designed to precisely irradiate tumours. This review aims to systematically outline the landscape of advances in RDCs for lung cancer, and provides a forward‑looking perspective on next‑generation RDCs. This analysis was based on preclinical and clinical data retrieved from PubMed and ClinicalTrials.gov, with all records reviewed up to January 2026. Studies were exhaustively surveyed across most radionuclides relevant to RDCs in lung cancer, following the periodic table to ensure comprehensive coverage. In lung cancer, a total of 66 RDCs have been screened, with 30 having entered early‑phase clinical trials. Among completed trials, RDCs underwent a transition from initial 131I/90Y‑labelled antibodies toward 177Lu‑labelled somatostatin receptor (SSTR)‑targeting peptides. SSTR remains the dominant target, with a notable shift from agonists to antagonists. Meanwhile, fibroblast activation protein (FAP), epidermal growth factor receptor (EGFR), and programmed death‑ligand 1 (PD‑L1) are receiving growing attention. Peptides and antibodies are equally employed, with bispecific antibodies (bsAbs), single‑domain antibodies (sdAbs), and cyclic peptides advancing rapidly. Furthermore, nanoparticles (NPs) offer versatile platforms, and pretargeting or dual‑targeting strategies are being developed to improve both efficacy and safety. Crown chelators and bipyridine derivatives provide more stable chelating options. Although 177Lu remains the mainstay, α emitters and emerging mixed‑decay radionuclides like 161Tb are gaining ground. Combination therapies are also being investigated to enable first‑line application. Despite recent progress in RDC development, challenges such as off‑target toxicity, radiation resistance, and radionuclide production remain. Next‑generation RDCs hold promise to overcome these barriers by novel radionuclides, personalised dosimetry, multifunctional delivery platforms, and multidrug combination strategies. Collectively, these innovations will propel RDCs into a personalised, precision theranostic platform for lung cancer.

Thymic epithelial tumors (TETs), including thymic carcinoma and thymoma, are rare malignancies lacking both effective therapies and validated biomarkers to guide treatment. Here, we report the first 3D (three-dimensional) bioprinted organoid model of TETs, established through a proteomic data-driven biomaterial design strategy. Patient tumor tissues were first decellularized and analyzed by proteomics to determine their extracellular matrix (ECM) composition. The results revealed distributions of ECM proteins which guided the formulation of photocurable bioinks. The resulting 3D-bioprinted organoids supported primary TET cell proliferation, and more faithfully replicated the biophysical properties and molecular characteristics of native tumors than traditional Matrigel-cultured organoids. Leveraging this biomimetic platform, we conducted high-throughput drug screening and identified lurbinectedin as a potent therapeutic candidate for TETs. Transcriptomic profiling revealed its anti-TET mechanism. Integrating RNAseq data with TCGA survival analysis further identified PBX3, REPS2, and CXCR4 as potential efficacy-predictive biomarkers. This study establishes a translational framework linking 3D bioprinted TET models with biomarker discovery, offering a standardized platform for precision drug screening and mechanistic exploration in thymic epithelial tumors.

Innovative chimeric antigen receptor (CAR) T cell designs and combinational approaches are needed for enhancing therapeutic effectiveness in solid tumors. We developed and assessed a novel dual-targeting CAR-T therapy that combines an αPDL1.CD28 chimeric receptor with a second-generation αCD133 CAR to target CD133+ tumors. The αPDL1.CD28 structure activated the CD3ζ signaling in cis by clustering with αCD133 CAR via CD28 dimerization. Binding to programmed cell death ligand-1 (PD-L1) through αPD-L1 CAR improved the CD133-targeted cytotoxic function of T cells by enhancing activation signals and countering inhibitory signals. Combination with programmed cell death receptor-1 (PD-1) blockade further disrupted the PD-L1/PD-1 inhibitory signal, achieving prolonged therapeutic efficacy. Moreover, radiation pre-conditioning (10 Gy/1 fraction or 4 Gy/2 fractions) maximized the antitumor effects of CAR-T plus PD-1 blockade, inducing complete tumor regression in mice. Radiation induced a unique tissue-resident memory CAR-T cell phenotype with high CXCR6 and CD103 expression. As the ligand of CD103, E-cadherin expression increased in tumor cells after irradiation, potentially mediating E-cadherin-CD103 interactions between tumor cells and tissue-resident memory T cells. Our study introduces a novel dual-targeting CD133/PD-L1 CAR-T cell and further demonstrates the efficacy and rationale of the triple-combination approach in solid tumors.

The optimal strategy for combining radiotherapy (RT) and immunotherapy remains under intensive investigation. Here we developed TRIDENT (Triple Radio-Immunotherapy-Driven ENhanced Therapy), a novel triple-modality regimen combining immunomodulatory low-dose RT (LDRT) to large tumor(s), immunogenic high-dose RT (HDRT) to small tumor(s), and PD-1 blockade. In our phase I trial of 29 patients with treatment-naïve, PD-L1-positive advanced non-small cell lung cancer (NSCLC), TRIDENT achieved a median overall survival (mOS) of 51.3 months (95% CI, 20.7-not reached), higher than outcomes typically reported with contemporary standard (chemo)immunotherapy. This durable survival signal was corroborated in an independent real-world cohort of 97 patients with advanced lung cancer (mOS: 41.5 months; 95% CI, 26.3-63.7). Mechanistically, TRIDENT elicited neutrophil-dependent, systemic antitumor immunity and induced a distinct population of antitumor TNF-α⁺ neutrophils marked by increased MHC and costimulatory molecule expression. Neutrophil recruitment was driven by the CXCL-CXCR2 axis, and polarization toward an antitumor state was programmed by treatment-induced IFN-γ and GM-CSF. TNF-α⁺ neutrophils enhanced CD8⁺ T-cell function via ICAM-1-LFA-1 interactions, and adoptive transfer confirmed their intrinsic antitumor activity in vivo. Spatial transcriptomics of patient tumor tissues further identified a TNF-α+ neutrophil-effector CD8+ T-cell niche after TRIDENT, providing a stimulatory signal to effector CD8⁺ T cells. In line with these mechanistic findings, clinical biomarker analyses linked neutrophil number with prolonged survival. TRIDENT activates an RT-driven neutrophil-CD8⁺ T-cell axis and promotes survival-associated neutrophil activation. These mechanistic insights, coupled with durable survival in our phase I trial, position TRIDENT as a promising strategy for metastatic NSCLC currently undergoing randomized phase II evaluation. Our study also highlights TNF-α+ neutrophils as a promising therapeutic strategy to enhance antitumor efficacy.

ABSTRACT In biological systems, enzymes achieve efficient catalysis by precisely assembling multinuclear metal‐oxo bridges, such as Fe─O─Fe motifs, under physiological conditions. However, constructing such structures in synthetic systems, particularly under mild aqueous conditions, remains challenging. Here, we report a self‐assembled helical polymer that creates a protein‐like microenvironment and enables the biomimetic construction of Fe─O─Fe structures in a synthetic polymer system under mild, neutral aqueous conditions. This strategy increases the stability constant of iron coordination by two orders of magnitude and endows the resulting complex with pH‐gated catalytic behavior: the complex remains catalytically inert under neutral conditions but exhibits more than 20‐fold enhanced peroxidase‐like activity in the weakly acidic tumor microenvironment. Moreover, oxo‐bridge formation significantly enhances near‐infrared absorption, enabling a robust photothermal effect. Without any exogenous drug payload, the complex selectively induces ferroptosis and immunogenic cell death in tumor cells, leading to complete tumor eradication in a mouse model. This work establishes a biomimetic strategy for constructing metal‐oxo‐bridged clusters and provides mechanistic insights into the structure‐function relationships of metalloprotein‐inspired materials.

Abstract Background: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine carcinoma characterized by rapid progression and a high relapse rate. Although the combination of immune checkpoint inhibitors (ICIs) with radiotherapy (RT) has improved patient outcomes, acquired resistance remains inevitable. This study aims to elucidate the underlying mechanisms of radioimmunotherapy resistance and explore potential novel strategies. Methods: We established a murine SCLC model of acquired radioimmunotherapy resistance by subjecting tumor-bearing mice to multiple cycles of RT + ICI until resistance developed. Subsequently, longitudinal single-cell RNA sequencing (scRNA-seq) analysis of tumor specimens was performed to validate the findings. The DNA damage repair (DDR) pathway was investigated using Western Blot, ELISA, and Transwell assays. The efficacy of adding PARP inhibitor (PARPi) to RT+ICI was evaluated in vivo. Results: Analysis of the radioimmunotherapy-resistant murine SCLC model revealed that enhanced DDR activity, elevated CCL2 secretion, and increased of infiltration of CCR2+ myeloid-derived suppressor cells (MDSCs), which were further validated by longitudinal scRNA-seq. Targeting the CCL2-CCR2 axis significantly delayed tumor relapse following RT + ICI treatment. Next, in vitro, combining PARPi with RT synergistically suppressed DDR activation and inhibited CCL2-dependent MDSC migration. In vivo, concurrent administration of PARPi with RT + ICI was essential for achieving better tumor control and survival benefit compared with RT + ICI treatment, whereas delayed intervention of PARPi proved ineffective. Tumor microenvironment analysis demonstrated that the triple therapy (RT + ICI + concurrent PARPi) effectively suppressed the DDR pathway, significantly reduced CCR2+ MDSC infiltration, and increased effector T cell recruitment. Conclusion: DDR-driven CCL2 secretion recruits CCR2+ MDSCs to mediate radioimmunotherapy resistance in SCLC. PARPi disrupts this axis through dual blockade of tumor DDR and MDSC recruitment. Our data revealed that the combination of concurrent PARPi with radio-chemo-immunotherapy as first line therapy in ES-SCLC is worth exploring and a prospective clinical trial is ongoing (NCT06217757). Citation Format: Zhuoran Yao, Hui Wang, Kai Kang, Min Yu, Feifei Na, Ren Luo, Linglu Yi, Ruizhan Tong, Jianxin Xue, You Lu. Targeting DNA damage repair pathway and CCR2+ myeloid cell to overcome radioimmunotherapy resistance in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 250.

ObjectiveTo research whether radiation-induced liver damage and fibrosis could be mitigated by resveratrol (RSV) and to elucidate its underlying mechanism.MethodsA radiation-induced liver damage (RILD) model of murine was constructed. RSV was used as an intervention agent. The effects of RSV on inflammatory reaction, apoptosis, senescence, fibrosis, survival, and liver functions were detected by β-Gal, Sirius red, Masson's trichrome, and Tunnel staining using an automated biochemistry analyzer. The protein expression levels of P16 and P21 were detected by Western blot.ResultsRSV alleviated inflammatory injury of RILD mice. RSV decreased the serum pro-inflammatory cytokines of RILD mice. RSV alleviated radiation-induced hepatocellular senescence. The protein expression levels of P16 and P21 in RILD mice were decreased with RSV administration. RSV decreased the number of apoptotic cells in the early stage of RILD. RSV alleviated liver fibrosis and liver function in RILD mice.ConclusionsRSV reduces RILD and fibrosis, and may be related to inhibiting cellular aging and reducing inflammation.

Background:Lung adenocarcinoma (LUAD) sustains an immunosuppressive tumor microenvironment (TME) via stromal-immune interactions. Efferocytosis regulates immune suppression and tissue homeostasis, yet biomarkers stratifying its TME states are lacking in LUAD, hindering precision therapy. This study aimed to investigate efferocytosis-associated immune regulation with both causal and prognostic relevance in LUAD, and to identify key biomarkers with potential implications for tumor stratification and therapeutic guidance. Methods:Gene expression profiles from The Cancer Genome Atlas (TCGA) LUAD cohort and Genotype-Tissue Expression (GTEx) underwent differential expression analysis. Efferocytosis-related genes (ERGs) from GeneCards were intersected to identify LUAD-associated candidates. Mendelian randomization (MR) and colocalization evaluated causal ERG-LUAD relationships. Risk-related ERGs were systematically analyzed for expression, biological functions, prognosis, and immune interactions. Single-cell RNA sequencing (scRNA-seq) mapped cellular expression specificity of core ERGs. Machine learning prognostic models (S1PR5-enriched NK cell-related prognostic signature, SENRPS) were developed and validated across independent cohorts. Results:S1PR5 expression was significantly lower in tumor tissues from LUAD patients compared to healthy lung tissue, at both the transcript and protein levels. We identified S1PR5 as a dual biomarker serving both as a protective factor against LUAD pathogenesis and a prognostic marker for survival outcomes, linked to favorable prognosis and enhanced therapy sensitivity. ScRNA-seq localized S1PR5 to natural killer (NK) cells, enhancing the anti-tumor activity of CD16+ NK cells and mediating interactions with antigen-presenting CEACAM8+ macrophages. The SENRPS model integrates molecular and cellular features for risk stratification and clinical decision-making. Conclusions:S1PR5 serves as a causal protective gene and prognostic biomarker governing cytotoxic immunity. SENRPS bridges TME dynamics to clinical risk prediction and therapeutic optimization, advancing LUAD precision oncology.

Background: To date, no direct comparisons have been performed to compare the effectiveness of all epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) against EGFR mutation-positive non-small cell lung cancer (NSCLC). This study aimed to investigate the efficacy and safety of EGFR-TKIs in patients with EGFR mutation-positive NSCLC. Methods: We conducted a network meta-analysis of randomized controlled trials comparing osimertinib, lazertinib, aumolertinib, befotertinib, furmonertinib, dacomitinib, afatinib, erlotinib, gefitinib, icotinib, and chemotherapy. Pooled estimations of progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and toxicity (grade > 3 adverse events) were performed within the Bayesian framework. Results: Twenty-three trials involving 11 treatments were included. All EGFR-TKIs improved PFS relative to chemotherapy, except for icotinib (hazard ratio [HR] = 0.61,95% confidence interval [CI]: 0.26-1.44). All EGFRTKIs demonstrated significant ORR benefits over chemotherapy. Osimertinib seemed to prolong PFS compared with icotinib (HR = 0.29, 95% CI: 0.1-0.86), gefitinib (HR = 0.39, 95% CI: 0.21-0.74), and erlotinib (HR = 0.53, 95% CI: 0.29-1.0). In addition, osimertinib showed favorable superiority in improving OS compared with chemotherapy (HR = 0.6, 95% CI: 0.43-0.82), gefitinib (HR = 0.61, 95% CI: 0.45-0.83), erlotinib (HR = 0.65, 95% CI: 0.48-0.89), and afatinib (HR = 0.65, 95% CI: 0.44-0.94). Among these regimens, afatinib showed the highest ORR (cumulative probability: 96.96%). Icotinib was associated with minimal toxicity among the EGFRTKIs, followed by furmonertinib and osimertinib. Moreover, the toxicity spectra differed among the EGFRTKIs. Subgroup analyses of patients with two common types of EGFR mutations indicated that furmonertinib possessed the greatest PFS benefit in patients with exon 19 deletion, and lazertinib showed the greatest PFS benefit in patients with Leu858Arg mutation. We also identified differences between EGFR-TKIs in prolonging PFS in patients with brain metastasis. Conclusions: Osimertinib is the first choice of treatment with considerable efficacy and safety for EGFR mutation- positive NSCLC. The treatments associated with the best PFS in patients with exon 19 deletions and Leu858Arg mutations were furmonertinib and lazertinib, respectively.

Metal ion-mediated redox process and protein folding are fundamental to numerous physiological functions. However, the mechanisms underlying copper ion interactions with macromolecules remain insufficiently understood, and the therapeutic potential of polymer-copper complexes is largely underexplored. Here, a biomimetic metallopolymer is reported in which copper ion coordination induces a conformational transition from β-sheet to α-helix, accompanied by oxidative self-encapsulation and fluorescence quenching. By leveraging the tunable intrinsic fluorescence of the polymer, the first systematic elucidation of the coordination interaction mechanism between polythiols and copper ions is presented. This interaction enhances the structural stability, catalytic efficiency, membrane activity, and drug loading capacity. Furthermore, the polymer-copper complex demonstrates tumor-activated fluorescence and dual enzyme-mimetic activities, enabling precise tumor imaging and multimodal therapeutic efficacy both in vitro and in vivo. This work provides new insights into the interactions between macromolecules and metal ions and establishes a versatile and intelligent nanosystem for advanced disease diagnostics and therapeutics.

INTRODUCTION:Lung cancer remains a leading cause of cancer-related deaths worldwide, with squamous lung cancer representing a significant subtype. Despite advancements in chemotherapy and immunotherapy, outcomes for patients with advanced squamous lung cancer remain suboptimal. Recent studies have shown that immunotherapy, particularly with programmed death receptor 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors, can improve survival rates, but challenges persist in achieving durable responses. Combining immunotherapy with radiotherapy has emerged as a promising strategy. Stereotactic body radiotherapy (SBRT) can enhance the immune response by inducing tumour-specific antigen release and promoting systemic immune activation, while low-dose radiation (LDRT) may further potentiate these effects by modulating the immune environment. This study explores a novel triple-combination approach using SBRT, LDRT, sintilimab and chemotherapy to optimise therapeutic efficacy and improve outcomes in locally advanced or metastatic squamous non-small cell lung cancer (sqNSCLC). METHODS AND ANALYSIS:This is a randomised, controlled, open-label, multicentre phase II clinical trial involving patients with locally advanced or metastatic sqNSCLC. Participants are randomised 1:1 into two arms: the experimental arm receives SBRT and LDRT combined with sintilimab and chemotherapy, while the control arm receives sintilimab with chemotherapy alone. Randomisation is stratified by PD-L1 expression and the presence of brain metastases. The primary endpoint is the objective response rate. Secondary endpoints include disease control rate, progression-free survival, overall survival and safety. Based on an expected ORR of 75% for the experimental group and 55% for the control, with a 20% difference detection at 80.1% power and a two-sided α level of 0.2, a total of 114 patients (57 per group, accounting for a 10% dropout rate) is required. ETHICS AND DISSEMINATION:The study protocol was approved by the Ethics Commission of Sichuan University West China Hospital (2023-1582), Medical Ethics Committee of Affiliated Hospital of North Sichuan Medical College (2024ER543-1), Ethics Committee of The Second Affiliated Hospital of Chongqing Medical University (2024-54-2), Ethics Committee of Union Hospital (Tongji Medical College, Huazhong University of Science and Technology) (2024-1052-02), Ethics Committee of Sichuan Cancer Hospital (SCCHEC-02-2025-069), Clinical Trial Ethics Committee of Deyang People's Hospital (2025-03-012-H01), and Ethics Committee of Guizhou Provincial People's Hospital (2025-108). Results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION:NCT06121505.