Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare yet highly aggressive subtype of non-small cell lung carcinoma (NSCLC) with limited therapeutic options. We conduct a comprehensive proteogenomic analysis of LCNEC using tumors and paired normal adjacent tissues from 107 patients (81 pure LCNEC and 26 combined LCNEC). APOBEC mutational signatures strongly correlate processes of tumor initiation and immune suppression, and KEAP1 mutations correlate with metabolic reprogramming in LCNEC combined with NSCLC. A conflicting relationship is observed between neuroendocrine and immune phenotypes. We identify three LCNEC subtypes with unique prognosis features, microenvironment dysregulation, genetic alterations, and potential therapeutic targets. Interleukin-33 (IL-33) emerges as a critical therapeutic biomarker associated with enhanced T cell infiltration and antitumor activity. We further optimize recombinant IL-33 (rIL33) with site-directed mutagenesis and develop PEGylated rIL33, demonstrating its prolonged circulation time in cynomolgus monkeys and superior immune agonist activity in mouse models. Overall, this study offers insights into LCNEC biology and provides promising innovative immunoagonist therapy strategies for lung cancer.

Pulmonary sarcomatoid carcinoma (PSC) is a rare yet highly invasive type of lung cancer that remains poorly characterized. Here, we conduct multi-omics analyses of PSC by integrating whole-exome sequencing, transcriptomic, proteomic, and phosphoproteomic data from 86 PSC patients, alongside single-cell RNA sequencing (scRNA-seq) data from 3 patients receiving neoadjuvant chemoimmunotherapy. We find an elevated ferroptosis suppression signature in PSC tumors and demonstrate their vulnerability to ferroptosis by targeting FTL and SLC3A2. Immune landscape characterization reveals an association between cold tumors, pleomorphic carcinoma, and PTEN mutations. Proteomic profiling identifies three distinct patient subtypes, each exhibiting unique features regarding microenvironment dysregulation, genetic alterations, and potential therapeutic targets. scRNA-seq analysis suggests roles of epithelial-mesenchymal transition in the progression from carcinoma cells to sarcomatoid cells and in immunotherapy resistance in PSC. Altogether, this multi-omics characterization of PSC serves as a rich resource for investigating mechanistic insights and identifying potential therapeutic targets.

The cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial cytosolic DNA-sensing pathway that bridges innate and adaptive immunity. Extensive research has demonstrated the important roles of cGAS-STING signaling in various aspects, including antimicrobial defense, genomic stability, and immune homeostasis. However, this pathway has a double-edged effect in cancer. On the one hand, activation of the cGAS-STING pathway generates antitumor effects by enhancing antigen presentation via dendritic cells, reinforcing tumor immune surveillance, and promoting cytotoxic effects of CD8 + T cells and natural killer cells. In contrast, persistent stimulation of cGAS-STING signaling drives chronic inflammation, which results in immunosuppressive cell accumulation, enhanced angiogenesis, and tumor cell proliferation and metastasis. In the tumor microenvironment, the cGAS-STING pathway not only coordinates a complex network involving immune cells, cancer-associated fibroblasts, and endothelial cells but also engages in noncanonical regulatory functions in ferroptosis, pyroptosis, and nuclear DNA repair. These multifaceted effects identify cGAS-STING signaling as a potential driver of tumor adaptation and a promising immunotherapeutic target. Current clinical strategies for STING agonists or combination therapies with immune checkpoint inhibitors have shown encouraging, yet variable, outcomes, highlighting multiple challenges, including dose optimization, immune tolerance, and patient heterogeneity. A deeper mechanistic understanding and precise spatiotemporal regulation of this pathway are critical to fully harness its therapeutic value in cancer.

Beta score (sheet1), mapping ratio (sheet2), and essential genes list (sheet3) of CRISPR screens.

Single-strand break repair genes (sheet1), double-strand break repair genes (sheet2), and DNA methylation related genes (sheet3).

Neuroendocrine (NE) prostate cancer (NEPC) is an aggressive and lethal subtype of prostate cancer. It is typically characterized by the expression of NE markers and the loss of androgen receptor expression. De novo NEPC is rare, accounting for <2% of all prostate cancer cases at diagnosis. More commonly, NEPC arises from prostate adenocarcinoma following androgen deprivation therapy, with 20‑25% of metastatic castration‑resistant prostate cancers undergoing NE differentiation due to lineage plasticity. During this transition, pathways associated with epithelial‑mesenchymal transition (EMT) and stemness are broadly activated, which is considered to be a key driver of NEPC's high metastatic potential, resistance to chemotherapy and radiotherapy and poor prognosis. EMT facilitates metastasis by enhancing cellular motility and invasiveness, while stemness properties contribute to post‑metastatic colonization, immune evasion, therapy resistance and cellular dormancy. As manifestations of cellular plasticity, these processes share overlapping molecular mechanisms. Targeting key regulators within these pathways may offer promising therapeutic strategies for NEPC.

Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer, and it demonstrates limited treatment options and worse survival. Identifications of a prognostic model and chemoresistance mechanism can be helpful for improving stratification and guiding therapy decisions. The integrative development of machine learning-based models reveals a random survival forest (RSF) prognostic model for LUSC. The 12-gene RSF model exhibits high prognostic power in more than 1,000 LUSC patients. High-risk LUSC patients are associated with worse survival and the activation of the epithelial-mesenchymal transition pathway. Additionally, high-risk LUSC patients are resistant to docetaxel or vinorelbine treatment. In vitro and in vivo drug sensitivity experiments indicates that high-risk HCC15/H226 tumour cells and cell line-derived xenograft models are more resistant to vinorelbine treatment. Furthermore, the combination of chemotherapy with transforming growth factor-β inhibition augments antitumour responses in LUSC tumours. Our study provides valuable insights into prognosis stratification and the development of therapeutic strategies for LUSC. A random survival forest prognostic model for the risk assessment of newly diagnosed LUSC patients may guide the application of chemotherapy in LUSC.

Genes’ average Δβ-scores across all cancer cell lines (sheet1); Gene sets enrichment for positively (sheet2) / negatively (sheet3) selected genes in CRISPR screen. GSEA was used to perform the enrichment analysis; sgRNA sequences of AAVS1, PAXIP1, TP53BP1, XRCC4, RAD50, RAD51, BRCA1, BRCA2 (sheet4).

Raw count table for RNA-seq.

The PD-L1 immune checkpoint inhibitors (ICIs) improve the survival in small cell lung cancer (SCLC), yet only a small subset experiences durable responses, possibly due to less than 20% of SCLC expressing PD-L1 > 1% of tumor cells. Evaluating the expression of checkpoint molecules in SCLC may identify molecules beyond PD-L1 that are amenable to ICIs. We firstly evaluated 28 immune checkpoint molecules via RNA-seq data in the Cancer Cell Line Encyclopedia database. Next, our in-house proteogenomic dataset and other publicly available datasets, including microarray data, RNA-seq data, and scRNA-seq data from tumor specimens, were enrolled. IMpower133 and Roper et al. datasets were employed to evaluate LAG-3 as a predictive marker of immunotherapy efficacy in SCLC. Finally, Immunohistochemistry was performed to verify LAG-3 expression in SCLC. LAG-3 exhibited higher expression in SCLC cell lines than in lung adenocarcinoma, lung squamous cell carcinoma, and melanoma. Analysis of SCLC tumor and paired normal samples revealed the highest overexpression of LAG-3 in SCLC tumors among compiled checkpoint molecules. Higher LAG-3 expression correlated with longer overall survival and served as an independent favorable prognostic factor. Furthermore, higher LAG-3 expression was associated with increased MHC-I expression, immune cell infiltration, and certain immune checkpoints' expression. Increased LAG-3 expression correlated with ICI benefit in SCLC patients. scRNA-seq analysis revealed that LAG-3 was primarily expressed in the tumor cells and T cells, and LAG-3 expression was higher than that of PD-1, CD274, and CTLA-4 on the CD8+ T cells. LAG-3 might serve as a potential biomarker in SCLC.

Expression of DSB repair genes especially resistant or non-resistant DSB repair genes in TCGA datasets with SSB repair genes mutation and deletion.

IFN-γ sensitivity of cancer cells (n = 43) from CCLE (sheet1); Gene sets enrichment for highly expressed gene sets in IFN-γ resistant/sensitive cell lines using CCLE transcriptomic dataset (sheet2-3).

Cox regression model of IFNG expression on patients’ survival in TCGA and Available expression data of ICB treatment.

The efficacy and safety of induction-immunotherapy followed by surgery for unresectable Stage III non-small cell lung cancer (NSCLC) remain challenging. In this open-label, single-center, phase II clinical umbrella trial (ChiCTR2000035367), 100 unresectable Stage III NSCLC patients are enrolled. Patients with PD-L1 expression ≥ 50% but contraindications to anti-angiogenic therapy receive immuno-monotherapy. Patients with PD-L1 expression ≥ 1% and no contraindications to anti-angiogenic therapy receive immunotherapy plus anti-angiogenesis therapy. Patients with PD-L1 expression between 1% and 49%, contraindications to anti-angiogenic therapy, or negative/unknown PD-L1 expression receive chemoimmunotherapy. The primary endpoint is the major pathological response (MPR) rate. Among 47 surgically-treated patients, the MPR rate is 61.7% (95% confidence interval [CI]: 46.4%-75.5%), achieving the prespecified endpoint. For secondary endpoints, the objective response rate for all patients is 54.0% (95% CI: 43.7-64.0). The median event-free survival is 29.9 months (95% CI: 17.0-42.7). Most common adverse event is anemia (49.0%). Exploratory transcriptomic analyses reveal Bone Marrow Stromal Cell Antigen 1 (BST1) as a promising biomarker for response to chemoimmunotherapy. Generally, for unresectable stage III NSCLC patients, anti-PD1 based induction-therapy according to PD-L1 expression and contraindication to antiangiogenic therapy followed by surgery is a feasible option. Induction-immunotherapy before surgery has been suggested for patients with unresectable stage III non-small cell lung cancer (NSCLC). Here, the authors report a phase 2 umbrella clinical trial where patients with unresectable stage III NSCLC receive anti-PD1-based induction-therapy based on PD-L1 expression and contraindications to antiangiogenic therapy.

Background:Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) exhibited a higher propensity for lymph node metastasis (LNM). This study aimed to investigate risk factors of occult lymph node metastasis (OLNM) and recurrence in resectable ALK-rearranged NSCLC patients. Methods:This retrospective analysis included patients with ALK-rearranged NSCLC receiving lung resections at Shanghai Pulmonary Hospital from June 2016 to August 2021. Logistic regression analysis was used to ascertain predictors of OLNM, and Cox regression analysis to identify risk factors of recurrence. Results:A total of 603 resectable ALK-rearranged NSCLC patients were included. The mean age was 55 years old. There were 171 patients (28.4%) pathologically confirmed to have LNM, 51.5% of which were occult. Logistic regression analysis identified clinical tumor size and computed tomography (CT) density as independent factors for OLNM. Cox regression analysis showed that pleural invasion and pathological tumor size were independent prognosticators for recurrence in pathologically nodal negative patients. Among pathologically nodal positive patients, adjuvant ALK-tyrosine kinase inhibitors (TKI) showed a similar recurrence-free survival (RFS) to chemotherapy (hazard ratio, 0.454; 95% confidence interval, 0.111-1.864). Conclusions:Assessing the potential risk of OLNM is required for ALK-rearranged NSCLC patients with large tumors characterized by high CT densities. Patients with large pathological tumor size or pleural infiltration should be closely monitored despite being pathologically nodal negative. Additionally, adjuvant ALK-TKI may present a comparable RFS to chemotherapy in pathologically nodal positive patients.

Lung adenocarcinoma (LUAD) is the most dominant histological subtype of lung cancer and one of the most lethal malignancies. The identification of novel therapeutic targets is required for the treatment of LUAD. Here, we showed that MYC-associated zinc-finger protein (MAZ) is upregulated in LUAD tissues. MAZ expression levels are inversely correlated with patient survival. Silencing of MAZ decreased tumor proliferation and the expression of pro-tumorigenic chemokines and Galectin-9 (Gal-9), an immune checkpoint molecule. The pro-tumorigenic chemokines and Gal-9 induce immune suppression by recruitment of myeloid cells and inhibition of T cell activation, respectively. Mechanistically, MAZ transcriptionally regulates KRAS expression and activates its downstream AKT-NF-κB signaling pathway, which is crucial for tumor progression and immune evasion. Additionally, in vivo animal models and bioinformatic analyses indicated that MAZ suppression could enhance the efficacy of immune checkpoint blockade (ICB) therapy for LUAD. Overall, our results suggest that MAZ plays an important role in regulating cell proliferation and immune evasion via KRAS/AKT/NF-κB signaling in LUAD. Our findings offer a candidate molecular target for LUAD therapy, with implications for improving the efficacy of ICB therapy.

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Background: To investigate the expression levels and diagnostic value of glial cell line-derived neurotrophic factor (GDNF), carcinoembryonic antigen (CEA) and carbohydrate antigen199 (CA199) in patients with colorectal carcinoma (CRC). Methods: 50 CRC patients at our hospital from Feb. 2020 to Feb. 2021 were chosen as the malignant group, another 50 patients with benign colonic diseases were chosen as the benign group, and 50 healthy people who came to our hospital for physical examination during the same period were considered as the control group. Fasting peripheral venous blood was taken from all research subjects in the morning and tested by a fully-automated electrochemiluminometer to determine the GDNF, CEA and CA199 levels. The sensitivity and specificity of the combined detection of the three indexes for CRC were analyzed, and the receiver operating characteristic (ROC) curve was plotted to record the area under the curve (AUC). Results: The malignant group had remarkably higher CEA and CA199 levels (P<0.001) and a lower GDNF level (P<0.001) when compared with the benign and control groups. The sensitivity, specificity, positive predictive value and negative predictive value of the combined detection were 96.0%, 94.0%, 88.9% and 97.9%, respectively. Under combined detection, AUC (95% CI) = 0.950 (0.909-0.991), standard error = 0.021, and P<0.001. Conclusions: The combined diagnosis of serum GDNF, CEA and CA199 is a reliable method to improve the diagnostic accuracy of CRC, and this strategy can effectively reduce the missed diagnosis rate and has high application value in clinic.

BACKGROUND:Pulmonary large cell neuroendocrine carcinoma (LCNEC) represents an exceptionally aggressive and infrequent variant within the realm of non-small cell lung cancer, necessitating surgical intervention as the primary therapeutic approach. However, the postoperative management strategy for early-stage patients continues to be a subject of intense debate and uncertainty. METHODS:A retrospective analysis was conducted on a cohort of patients diagnosed with LCNEC who underwent surgical resection at Shanghai Pulmonary Hospital between July 2018 and June 2022. Comprehensive assessments, encompassing univariate and multivariate analyses, were performed to evaluate the prognostic significance of these indicators in patient clinical profiles, overall survival (OS), and disease-free survival (DFS). RESULTS:A comprehensive screening effort identified 171 patients with LCNEC, with 70 stage I patients meeting the criteria for inclusion in the final cohort. Of these, 11 patients (15.7%) presented with combined LCNEC, and 59 (84.3%) exhibited pure LCNEC. Univariate and multivariate analyses both unveiled that spread through air spaces (STAS) status emerged as an independent prognostic determinant for both DFS (P = .003) and OS (P = .013), whereas histologic subtype independently predicted OS (P = .011). Subgroup survival analyses further underscored that the advantageous effects of postoperative chemotherapy were significantly pronounced exclusively among STAS-positive patients, showcasing a statistically significant enhancement in DFS (P = .047) and OS (P = .018). CONCLUSIONS:STAS may serve as an adverse prognostic factor in stage I LCNEC patients, potentially offering guidance for postoperative chemotherapy decisions.