Triple-negative breast cancer (TNBC) is highly invasive and has limited effective treatment options. Here, we developed natural extracellular nanovesicles derived from Taxus leaves (TLENs), which share the same plant origin as that of paclitaxel (PTX), to explore their potential as a targeted therapy carrier for TNBC. Through nontargeted metabolomics, it was found that it contains a large amount of flavonoids, with naringenin being the most abundant compound, as confirmed by LC-MS/MS analysis. Experiments have shown that the nanovesicles have significant anti-TNBC effects and, more importantly, can improve sensitivity to paclitaxel. At the cellular level, TLENs are internalized by TNBC cells via macropinocytosis, triggering an intracellular surge of reactive oxygen species that activates the JNK/p38 MAPK signaling cascade, thereby driving apoptosis while inhibiting cell proliferation, epithelial-mesenchymal transition, and migration. Beyond direct cytotoxicity, the oral coadministration of TLENs and PTX fundamentally remodeled the tumor microenvironment. The treatment effectively reversed immunosuppression by promoting dendritic cell maturation and enhancing cytotoxic CD8+ T cell infiltration while concurrently depleting regulatory T cells (Tregs) and myeloid-derived suppressor cells. This work innovatively proposes a "homologous combination" strategy that combines TLENs derived from the same plant with PTX. This combination exhibits enhanced anti-TNBC effects that are greater than those of either agent alone, providing a novel combination therapy for the treatment of TNBC.

8010 Background: The phase III NEOTORCH trial demonstrated that perioperative toripalimab significantly improved event-free survival in stage IIIA–IIIB driver-gene-negative NSCLC, along with a favorable overall survival trend. However, the generalizability of randomized controlled trial (RCT) results to broader, more heterogeneous, real-world populations is uncertain. This study aimed to evaluate the effectiveness and safety of this regimen in routine clinical practice, providing essential evidence for treatment decisions. Methods: This nationwide, prospective, observational study in China consecutively enrolled patients with stage II-III NSCLC planned for perioperative treatment containing toripalimab. The primary endpoint was real-world event-free survival (rwEFS). Secondary endpoints included pathological complete response (pCR) rate, major pathological response (MPR) rate, objective response rate (ORR), R0 resection rate, real-world disease-free survival (rwDFS), real-world overall survival (rwOS), and safety. Results: Between December 9, 2024, and January 14, 2026, 1727 patients were enrolled from 221 tertiary and secondary hospitals across 28 provinces in China. Baseline characteristics: 82.8% male; 51.4% aged ≥65 years; ECOG PS 0/1/2 in 43.2%/54.4%/2.4%. Histology: 71.4% squamous, 18.3% nonsquamous, 10.3% NSCLC not otherwise specified. Clinical stage distribution: IIA (1.7%), IIB (10.4%), IIIA (52.8%), IIIB (33.0%), IIIC (2.1%). Of all enrolled patients, 542 (31.4%) were pending preoperative assessment. Surgery was not performed in 634 patients (36.7%); reasons included: other causes (64.9%), patient refusal (15.7%), surgical ineligibility (9.3%), disease progression (8.2%), and adverse events (1.9%). Ultimately, 551 patients (31.9%) underwent resection, with 503 having postoperative pathological assessment. The MPR rate was 67.0% (337/503) and the pCR rate was 39.6% (199/503). As of the data-cutoff, investigators reported 20 (1.2%) grade ≥3 or clinically significant treatment-emergent adverse events, with hematologic toxicities being most common. Immune-related adverse events were infrequent (four events: three grade 1–2 pneumonitis, one grade 3 rash). Conclusions: This is the largest prospective real-world study of perioperative immunotherapy in NSCLC to date. Its extensive geographic coverage and diverse patient population-including higher proportions of elderly patients, those with ECOG PS 1, and varied histologies-validate the effectiveness and manageable safety of perioperative toripalimab in routine practice beyond RCT settings. The significant pathological response rates observed support the clinical benefit of this regimen for a broad spectrum of stage II-III NSCLC patients, providing crucial evidence for real-world decision-making. Clinical trial information: ChiCTR2400091457.

Although immune checkpoint inhibitors (ICIs) have contributed to significant advances in the treatment of lung cancer, there is a lack of research investigating their efficacy in patients with non-small-cell lung cancer harboring NRG1 fusion genes. This retrospective study included data from patients diagnosed with NRG1 fusion-positive NSCLC, who underwent ICI treatment at the Shanghai Pulmonary Hospital and Shanghai Changzheng Hospital (Shanghai, China) between 2016 and 2025, in accordance with the Response Evaluation Criteria for Solid Tumors, version 1.1. Data from 20 patients were analyzed. The total objective response rate was 15.0

Although immunotherapy is approved for patients with high PD-L1 expression, optimal therapeutic strategies for PD-L1-negative populations remain undefined. This study (ChiCTR2300071681) assessed the efficacy and safety of cadonilimab (PD-1/CTLA-4 bispecific antibody) plus chemotherapy in patients with PD-L1-negative advanced non-small-cell lung cancer (NSCLC). The primary endpoint, 12-month progression-free survival (PFS) rate, is 42.1% (95% CI, 29.6%-60.0%), which has reached the prespecified threshold. Secondary endpoints include a median overall survival of not reached, a median PFS of 9.7 months, an objective response rate of 66.0%, a disease control rate of 100.0%, and a median duration of response of 9.5 months. Grade ≥3 treatment-related adverse events occur in 26 (52.0%) patients. cfDNA methylation-based molecular response predicts the actual clinical response approximately 5 cycles earlier than conventional radiographic evaluation. Baseline differentially methylated fragments scores show a significant correlation with PFS, with low-risk patients demonstrating a longer median PFS compared to high-risk patients (11.4 months versus 6.9 months). Overall, first-line cadonilimab plus chemotherapy shows an encouraging efficacy with a manageable safety profile for challenging-to-treat PD-L1-negative advanced NSCLC, warranting further evaluation in controlled studies.

Targeting immune checkpoints, specifically programmed death 1, has significantly improved clinical outcomes in non-small cell lung cancer. However, only a proportion of patients benefited from immune checkpoint blockades (ICBs) therapy. Thus, identifying novel biomarkers to better select responders to ICBs is critically important in clinical practice. This retrospective study included two cohorts, a discovery cohort (n = 24) and a validation cohort (n = 21) of lung adenocarcinoma (LUAD) patients treated with ICB at Shanghai Pulmonary Hospital between April 2016 and November 2019. Formalin-fixed paraffin-embedded tissue samples were collected for RNA sequencing. Additionally, a TCGA dataset (GSE135222) and a clinical study dataset (POPLAR) were utilized as external validation and test sets, respectively. In the discovery cohort, cilia-associated pathways were significantly enriched in LUAD patients with non-durable benefit. A three-gene cilia-associated signature (TMEM100, DNAH3, and NEFH) was established and effectively predicted resistance to ICB treatment (discovery cohort, Hazard Ratio [HR, 95

Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor receptor 2 (HER2)-targeting antibody–drug conjugate that has demonstrated encouraging efficacy and a manageable safety profile in the second-line or later setting for non-small cell lung cancer (NSCLC) harboring HER2 mutations. While T-DXd was approved for treating patients with locally advanced or metastatic HER2-mutant NSCLC in China, real-world data on its use in Chinese clinical practice are lacking. This study will collect real-world data on T-DXd to evaluate its effectiveness and safety in Chinese patients with HER2-mutant metastatic NSCLC, thereby providing additional evidence to the oncology community in China. RERUN is a prospective, multicenter, observational cohort study conducted at approximately 30 sites in China. Approximately 150 adult patients (≥ 18 years) with pathologically documented unresectable and/or metastatic non-squamous NSCLC harboring any known activating HER2 mutation are currently being enrolled. The follow-up period will last approximately 6 months after the last patient is enrolled, when sufficient progression-free survival (PFS) maturity (approximately 60

Abstract Background Radiotherapy (RT) is a cornerstone treatment for lung cancer brain metastasis (LCBM), yet acquired radioresistance frequently leads to recurrence. The molecular and metabolic mechanisms underlying this adaptive evolution at single-cell resolution remain poorly defined. Methods Patient-derived organoids (PDOs) from LCBM tissues were established to model clinical radiation responses. Paired pre- and post-RT samples underwent single-cell RNA sequencing (scRNA-seq) to delineate transcriptional, metabolic, and regulatory alterations associated with radioresistance. Results Single-cell analysis revealed substantial population remodeling following RT, characterized by depletion of proliferative cells and enrichment of a resilient Hypoxic-EMT subpopulation. Pseudotime analysis demonstrated lineage plasticity, showing a transition from proliferative to mesenchymal states. Mechanistically, a viral mimicry response involving NF-κB and STAT signaling supported stress adaptation. Resistant cells exhibited a hypermetabolic phenotype marked by metabolic plasticity, including hybrid bioenergetics coupling glycolysis with oxidative phosphorylation, enhanced lipid turnover via simultaneous fatty acid synthesis and degradation, and increased glutathione metabolism for reactive oxygen species buffering. Pharmacogenomic profiling indicated concurrent chemotherapy resistance but collateral sensitivity to PI3K/MEK inhibitors and epigenetic therapies. Conclusions These findings provide a high-resolution atlas of radioresistance in LCBM and suggest that targeting the Hypoxic-EMT niche or oxidative-antioxidant balance may overcome therapeutic resistance.

Plant-derived nanovesicles have emerged as promising vectors for cross-species signal transmission, enabling them to enter animal cells via endocytosis and offering new insights into the mechanisms underlying the bioactivity of medicinal herbs. Pinellia ternata, a traditional Chinese medicinal plant, shows diverse pharmacological properties, including immunomodulatory and anti-tumor effects, though its mechanism of action remains to be fully elucidated. In this study, nanoscale exosome-like vesicles (∼150 nm in diameter) were isolated and characterized from fresh Pinellia roots, referred to as Pinellia-derived exosome vesicles (PEVs). PEVs induced immune activation and promoted M1-like polarization of macrophages. Transcriptomic analysis of THP-1-derived macrophages revealed that PEV treatment significantly inhibited the expression of key serine synthesis genes, PHGDH, PSAT1, and PSPH, and activated the JAK-STAT signaling pathway. Functional assays demonstrated that PEVs inhibited the proliferation of lung cancer cells by increasing macrophage-mediated immune responses in the tumor microenvironment and arresting the S phase of the cell cycle in tumor cells, particularly in tumors with high expression of serine synthesis related genes. These findings suggest that PEVs modulate macrophage polarization by regulating the serine synthesis/ JAK/STAT pathway, contributing to tumor suppression. This study provides a new therapeutic approach by integrating the bioactivity of traditional Chinese herbal medicine with modern nanotechnology for cancer treatment.

SYS6010 is an antibody-drug conjugate targeting epidermal growth factor receptor (EGFR). We report the results of a phase 1 trial (ChiCTR2300072141) of SYS6010 in patients with non-small cell lung cancer (NSCLC). A total of 236 patients were treated. One dose-limiting toxicity occurred at 6.4 mg/kg; therefore, 4.2, 4.5, and 4.8 mg/kg were selected for cohort expansion. Treatment-related adverse events (TRAEs; any/grade ≥ 3) occurred in 99.6%/57.2% of patients. Common grade ≥3 TRAEs included neutropenia (30.9%), leukopenia (25.0%), and thrombocytopenia (17.4%). Objective response rate was 34.7% in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) and platinum chemotherapy, 45.7% in EGFR-mutant NSCLC treated with EGFR TKIs, 20.0% in EGFR wild-type squamous NSCLC, and 35.7% in EGFR wild-type non-squamous NSCLC. Median progression-free survival and overall survival were 7.6 and 19.4 months, respectively, in EGFR-mutant NSCLC treated with EGFR TKIs and platinum chemotherapy. Overall, SYS6010 shows a manageable safety profile and encouraging antitumor activity in previously treated, advanced NSCLC.

Purpose:In this study, we report the design and evaluation of Anlo@MOF-Lipo (AML), a liposome coated, small sized MIL-101(Fe) metal-organic framework (MOF) for targeted delivery of the multi target tyrosine kinase inhibitor anlotinib in lung cancer treatment. Methods:In detail, the biomimetic liposome shell enhances nanoparticle biocompatibility, while the MIL-101(Fe) core enables pH responsive release of Fe3⁺ under acidic tumor conditions, triggering Fenton-like reactions and generating cytotoxic reactive oxygen species. Anlotinib is encapsulated within the MOF pores for sustained, intratumoral release, suppressing the growth of tumors. Results:Characterization confirmed uniform liposome coating and sustained anlotinib release of AML. In vitro, AML demonstrated superior cellular uptake and cytotoxicity in lung cancer cells. In a murine subcutaneous tumor model, AML treatment achieved a greater tumor volume reduction than free anlotinib, with no observable systemic toxicity. Furthermore, in the orthotopic lung cancer model, AML achieved the most pronounced therapeutic efficacy among all treatment groups. Conclusion:This dual mode therapeutic strategy-combining targeted chemotherapy with oxidative stress induction-highlights the potential of AML as a promising nanomaterial for improving lung cancer treatment.

With the wide application of low-dose spiral computed tomography and the advancement of imaging technology, the detection rate of pulmonary nodules has significantly increased. However, the traditional "one-size-fits-all" management strategy has been unable to meet the needs of precise diagnosis and treatment. This expert consensus was initiated by Professor Chunxia SU’s team and Professor Chang CHEN’s team from Shanghai Pulmonary Hospital and jointly formulated by experts from multiple disciplines including oncology, respiratory medicine, thoracic surgery, interventional medicine, radiology, and pathology. The aim is to provide scientific and practical decision-making references for clinical controversies that are less addressed or have differences in existing guidelines. The consensus uses the GRADE method for evidence assessment and forms 18 recommendations through two rounds of Delphi questionnaire surveys, focusing on differentiated screening for special populations, artificial intelligence assisted diagnosis, robot-assisted puncture, application of molecular markers, active monitoring of low-risk nodules, timing of invasive intervention, termination conditions of follow-up, management strategies for multiple nodules, and selection of individualized lymph node dissection range and surgical methods for early-stage lung cancer. This consensus would provides supplementary guidance for the entire process of precise management of pulmonary nodules from screening to treatment, with expectation of improving the long-term survival rate of lung cancer patients while minimizing unnecessary medical interventions and enhancing the quality of life of patients.

AIMS:Lipid-associated macrophages are a specific subpopulation of macrophages that play a crucial role in cancer progression and treatment resistance. However, the functional impact of lipid-associated macrophages in lung adenocarcinoma (LUAD) remains poorly understood. This study aims to investigate the role and underlying mechanisms of lipid-associated macrophages in LUAD liver metastasis and resistance to osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). METHODS:Single-cell RNA sequencing (scRNA-seq) was performed on human lung tumor tissues from patients with primary LUAD and those with LUAD liver metastasis, which identified a novel subpopulation of stabilin-1 (STAB1)+ lipid-associated macrophages. The influence of STAB1+ lipid-associated macrophages on LUAD liver metastasis and osimertinib resistance was evaluated in vitro and in vivo. An in vitro co-culture system was established to investigate the interaction between LUAD cells and lipid-associated macrophages, and the mechanisms were analyzed by RNA-seq, Luminex multi-factor detection, Co-IP, in vivo, and rescue experiments. RESULTS:The subpopulation of STAB1+ lipid-associated macrophages was more abundant in liver metastatic LUAD tumors than in primary tumors. This lipid-associated macrophage subpopulation exhibited a stronger ability of lipid uptake from tumors and lipid droplet accumulation. We found that C-X-C motif ligand 12 (CXCL12) chemokine secreted by liver metastatic LUAD cells was responsible for recruiting circulating monocytes and subsequently inducing their differentiation into STAB1+ lipid-associated macrophages. STAB1 overexpression impaired the phagocytic ability of macrophage towards dying tumor cells by upregulating the signal regulatory protein α (SIRPα)-CD47 "don't eat me" signal. In tumor xenograft models, inhibition of STAB1+ lipid-associated macrophages effectively suppressed LUAD osimertinib resistance and liver metastasis. CONCLUSIONS:Our study demonstrates that STAB1+ lipid-associated macrophages contribute to LUAD liver metastasis and osimertinib resistance by impairing macrophage phagocytosis via the SIRPα-CD47 axis, opening a potential avenue for future research and treatment development.

Background: Following the 2021 first International Consensus on Severe Lung Cancer, global attention to patients with PS 2-4 has grown significantly. Recent advances in novel therapies, interventional techniques, and supportive care, along with emerging real world data, have expanded treatment opportunities for this population. To incorporate these advances, we have updated the consensus. Methods: A multidisciplinary panel comprising experts from oncology, radiation oncology, thoracic surgery, radiology, interventional medicine, respiratory medicine, critical care medicine, and nursing. After being presented with a comprehensive review of the current evidence pertaining to severe lung cancer and thorough discussions, the panel reached a consensus on 11 recommendations, each with over 70% expert agreement. Results: The 11 consensus points focused on definition and causes (n=2), assessment and general strategies (n=4), and specific treatment modalities (n=5) were updated or newly developed. This updated consensus emphasizes dynamic and precise detection, robust life support, flexible application of novel therapies, and MDT guided treatment adjustment based on PS dynamics. Early rehabilitation and comprehensive supportive care are integral to disease management. Conclusions: This consensus updates the definition, diagnostic evaluation, and treatment strategies, providing a practical framework for clinicians based on current evidence and multidisciplinary expert consensus. Prospective trials focusing specifically on patients with severe lung cancer are urgently needed.

Tumor metabolic reprogramming is a pivotal mechanism driving acquired resistance to programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade therapy. Under therapeutic pressure, tumor cells undergo extensive metabolic rewiring, encompassing enhanced glycolysis, altered amino acid metabolism, and reprogrammed lipid utilization. This metabolic plasticity intensifies nutrient competition within the tumor microenvironment (TME), leading to the accumulation of immunosuppressive metabolites such as lactate and kynurenine. These metabolites collectively impair effector T cell activation, proliferation, and cytotoxicity, while simultaneously facilitating the expansion and suppressive activity of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). In parallel, T cells often exhibit metabolic exhaustion, characterized by mitochondrial dysfunction, reduced oxidative phosphorylation, and impaired metabolic flexibility, which ultimately limits their persistence and anti-tumor efficacy despite checkpoint blockade. Moreover, the intrinsic heterogeneity and adaptability of tumor metabolism promote the selection of resistant subclones during immunotherapy, further undermining treatment durability. To overcome these barriers, emerging combinatorial strategies are focusing on integrating metabolic inhibitors, such as lactate dehydrogenase A (LDHA) and IDO1 inhibitors, with immune checkpoint blockade, or on metabolically engineering T cells to enhance their fitness. Future efforts should emphasize precise patient stratification, development of highly selective metabolic modulators, and rational design of combination therapies to improve both the efficacy and long-term durability of cancer immunotherapy.

Abstract Malignant tumors are major diseases that seriously threaten human health, and the unmet clinical demand for treatments in the field of oncology has been persistently large. The research and development of new antineoplastic drugs has become a powerful means to address this demand. The purpose of this guideline is to provide a systematic overview and summary of clinical research on antineoplastic drugs in terms of study format, trial staging, mechanism of action, ethical review, trial process, patient needs, and the evaluation of efficacy and adverse events. It provides practical suggestions and references to aid the fundamental role of clinical research on antineoplastic drugs, i.e., to address clinical needs and maximize patient benefits.

Molecular residual disease (MRD), detected through circulating tumor DNA, has emerged as a promising biomarker for surveillance in patients with early-stage non-small cell lung cancer (NSCLC) following curative-intent resection. Here we report the MRD analysis from the phase 3 EVIDENCE trial, which includes patients with stage II-IIIA resected EGFR-mutated NSCLC who have received either adjuvant icotinib or chemotherapy. A total of 1,352 plasma samples from 175 patients are analyzed using the MinerVa Prime assay, a personalized tumor-informed MRD platform. At the landmark timepoint, MinerVa Prime detects MRD positivity in 35.8% (38/106) of patients with stage III disease and 14.7% (10/68) of patients with stage II disease, with a longitudinal positivity rate of 47.4%. MRD-positive status is significantly correlated with inferior disease-free survival (DFS), both at landmark (hazard ratio [HR]: 4.44, P < 0.001) and during longitudinal monitoring (HR: 7.82, P < 0.001). Icotinib confers DFS benefits over chemotherapy in both MRD subgroups, enhancing MRD clearance in MRD-positive patients while reducing molecular recurrence in landmark MRD-negative patients. Longitudinal MRD shows a 91.3% negative predictive value, with a median lead time of 169 days prior to clinical recurrence. Among serial monitoring timepoints, MRD status at 24 weeks post-randomization demonstrates the highest prognostic value.

Abstract Background: KRAS mutations are the most frequent oncogenic drivers in non-small cell lung cancer (NSCLC), with the KRAS G12C variant accounting for nearly half of KRAS-mutant cases. While KRAS inhibitors show strong antitumor activity, their efficacy is often limited by adaptive and acquired resistance, highlighting the urgent need for effective combination strategies. The deubiquitinase USP7, frequently overexpressed in cancers and linked to malignancy, therapeutic resistance, and poor prognosis. However, its role in KRAS-mutant lung cancer remains unclear. Methods: USP7 mRNA and protein expression levels in human and mouse KRAS-mutant lung cancers were analyzed using TCGA data mining and immunohistochemistry (IHC) analysis. KRAS G12C-mutant NSCLC cells and in vivo xenograft models were treated with KRAS G12C specific inhibitor (GDC-6036) and USP7 inhibitor (P5091), either alone or in combination, to evaluate the combinatorial antitumor effects. Cell viability and apoptosis assays were performed to evaluate treatment outcomes. Western blotting and RNA sequencing (RNA-seq) analyses were conducted to investigate alterations in this related cancer signaling pathways and elucidate the underlying molecular mechanisms. Results: USP7 mRNA expression was found to be significantly elevated in human cancer tissues and cell lines compared with normal controls. Combination index (CI) analysis using the Chou-Talalay method showed CI < 1, confirming that the USP7 inhibitor synergistically enhanced the efficacy of the KRAS G12C inhibitor. Mechanistically, USP7 synergistically inhibits the KRAS feedback signaling pathways, possibly due to suppression of cell proliferation through the MAPK and AKT pathways in cancer cells. RNA-seq revealed that the combination treatment elicited broader and more pronounced pathway modulation, with simultaneous inhibition of proliferative mechanisms (MYC, MTORC1, G2M) and suppression of DNA repair pathways. In line with RNA-seq findings, low-dose KRAS or USP7 inhibitors did not trigger significant apoptosis, while the combination markedly enhanced apoptosis and delayed KRAS signaling reactivation. Importantly, in vivo xenograft studies further demonstrated that the combination therapy produced a markedly stronger antitumor effect, significantly suppressing tumor growth (reduced p-ERK and Ki-67) and inducing substantially higher levels of apoptosis (increased Caspase-3) compared with KRAS or USP7 inhibition alone. Conclusion: The combination of KRAS G12C and USP7 inhibitors significantly enhances the anticancer effect by suppressing KRAS feedback signaling, modulating multiple oncogenic and metabolic pathways, and promoting apoptosis in cancer cells, representing a promising novel approach to achieve durable therapeutic benefits of KRAS blockade in NSCLC, warranting further investigation. Citation Format: Yuanyuan Gao, Keqiang Zhang, Wendong Li, Chunxia Su, John Liu, Lilian Gu, Mahima Raul, Dan Raz. USP7 inhibitor synergistically enhanced the anticancer effect of the KRAS G12C inhibitor by effectively countering feedback signaling pathways​ [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 1885.

Abstract Background: Pulmonary carcinoids (PCs), encompassing atypical carcinoids (ACs) and typical carcinoids (TCs), represent a rare category of lung cancer characterized by low to moderate malignancy. However, there is a limited understanding of the genomic and immune characteristics associated with PCs on a global scale. Methods: This study enrolled 126 surgically resectable PC patients, comprising 44 ACs and 82 TCs. Next-generation sequencing utilizing a 578-gene panel was conducted and immunohistochemical staining for PD-L1 and CD8 was also carried out. Findings: The most frequently altered genes in PCs were identified as EGFR (n=16, 18%), KMT2C (n=11, 12%), LRP1B (n=10, 11%), MEN1 (n=10, 11%), and NOTCH2 (n=9, 10%). Dysregulation of the RTK/RAS, NOTCH, and PI3K pathways was commonly observed in these PCs. Our study unveiled that only 4.6% of the PC patients were identified as PD-L1 positivity, and TMB and CD8+ T cell infiltration were found to be low in early-stage PCs, as manifested by the “immune-excluded” or “immune-desert” microenvironment. We identified age, gender, TNM stage, tumor type, smoking status, TMB, and LRP1B mutation as indicators of poor prognosis. We found that for those surgically resectable early-stage PC patients with LRP1B mutation, patients exhibit an increased risk for tumor-related mortality and recurrence, and subsequently further proposed a molecular classification based on the status of LRP1B mutation. Interpretation: We depicted the genetic and immune landscape of PCs and proposed a LRP1B mutation based molecular classification. Our research offers novel insights into the biological mechanisms of PCs which contributes to the individualized treatment for PC patients. Citation Format: Song Xu, Lingling Zu, Ning Zhou, Jingya Wang, Xiongfei Li, Haixiang Yu, Sibo Peng, Chunxia Su, Dingzhi Huang. Genomic-immunophenotypic landscape of early-stage pulmonary carcinoid tumors and their prognostic implications [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 3889.

e20742 Background: The neuroregulin 1 ( NRG1 ) gene fusion is a rare but clinically significant target in non-small cell lung cancer (NSCLC). Recently, targeted therapies for NRG1 have been approved and incorporated into clinical guidelines. However, the underdetection of NRG1 fusions at the DNA level remains a considerable challenge. In recent years, DNA+RNA-NGS has been successively recommended in expert consensus documents and clinical guidelines, and has been reported to offer superior performance in detecting fusion genes in NSCLC. This study evaluates the detection rate of NRG1 fusions using DNA+RNA-NGS compared to DNA-NGS in NSCLC patients in a real-world setting, providing reliable evidence for clinical practice. Methods: This study enrolled Chinese NSCLC patients from March 2022 and November 2025. Among them, 5032 patients underwent DNA-NGS, while 11432 patients received DNA+RNA-NGS. The DNA+RNA-NGS approach involved extracting both DNA and RNA from the same tissue sample, with RNA reverse-transcribed into complementary DNA (cDNA) and then combined with DNA. Within a single reaction system, DNA-NGS was employed to identify SNVs/Indels while RNA-NGS targeted fusion genes. NRG1 fusion-positive cases were identified and analyzed separately within each cohort. Results: The results demonstrated a higher NRG1 detection rate in the DNA+RNA-NGS cohort (0.219%) compared to the DNA-NGS cohort (0.099%). Further analysis revealed that 36% (9/25) of patients in the DNA+RNA-NGS cohort harbored at least two NRG1 fusion variants, whereas only single fusions were detected in the DNA-NGS cohort. Among all identified fusion variants (n = 45), CD74 was the most frequent fusion partner (64.44%, 29/45), significantly higher than the 20%-30% reported in the literature, followed by ATP1B1 (17.78%, 8/45). Additionally, DNA+RNA-NGS identified a wider spectrum of fusion partners, while the relatively common partner ATP1B1 was not detected in the DNA-NGS cohort. Further examination of the breakpoints revealed that the NRG1 breakpoints were predominantly located in exon 5. Clinical characteristics analysis indicated that nearly all NRG1 fusion-positive patients were diagnosed with lung adenocarcinoma. Conclusions: In conclusion, DNA+RNA-NGS significantly enhances the detection capability of NRG1 fusions, providing critical insights for precision medicine.