Metabolic reprogramming evolves during cancer initiation and progression. However, thorough understanding of metabolic evolution from preneoplasia to lung adenocarcinoma (LUAD) is still limited. Here, we perform large-scale targeted metabolomics on resected lesions and plasma obtained from invasive LUAD and its precursors, and decipher the metabolic trajectories from atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC), revealing that perturbed metabolic pathways emerge early in premalignant lesions. Furthermore, three panels of plasma metabolites are identified as non-invasive predictive biomarkers to distinguish IAC and its precursors with benign diseases. Strikingly, metabolomics clustering defines three metabolic subtypes of IAC patients with distinct clinical characteristics. We identify correlation between aberrant bile acid metabolism in subtype III with poor clinical features and demonstrate dysregulated bile acid metabolism promotes migration of LUAD, which could be exploited as potential targetable vulnerability and for stratifying patients. Collectively, the comprehensive landscape of the metabolic evolution along the development of LUAD will improve early detection and provide impactful therapeutic strategies.

Background Immunotherapy has revolutionized cancer treatment, but most patients are refractory to immunotherapy or acquire resistance, with the underlying mechanisms remaining to be explored. Methods We characterized the transcriptomes of ~92,000 single cells from 3 pre-treatment and 12 post-treatment patients with non-small cell lung cancer (NSCLC) who received neoadjuvant PD-1 blockade combined with chemotherapy. The 12 post-treatment samples were categorized into two groups based on pathologic response: major pathologic response (MPR; n = 4) and non-MPR (NMPR; n = 8). Results Distinct therapy-induced cancer cell transcriptomes were associated with clinical response. Cancer cells from MPR patients exhibited a signature of activated antigen presentation via major histocompatibility complex class II (MHC-II). Further, the transcriptional signatures of FCRL4+FCRL5+ memory B cells and CD16+CX3CR1+ monocytes were enriched in MPR patients and are predictors of immunotherapy response. Cancer cells from NMPR patients exhibited overexpression of estrogen metabolism enzymes and elevated serum estradiol. In all patients, therapy promoted expansion and activation of cytotoxic T cells and CD16+ NK cells, reduction of immunosuppressive Tregs, and activation of memory CD8+T cells into an effector phenotype. Tissue-resident macrophages were expanded after therapy, and tumor-associated macrophages (TAMs) were remodeled into a neutral instead of an anti-tumor phenotype. We revealed the heterogeneity of neutrophils during immunotherapy and identified an aged CCL3+ neutrophil subset was decreased in MPR patients. The aged CCL3+ neutrophils were predicted to interact with SPP1+ TAMs through a positive feedback loop to contribute to a poor therapy response. Conclusions Neoadjuvant PD-1 blockade combined with chemotherapy led to distinct NSCLC tumor microenvironment transcriptomes that correlated with therapy response. Although limited by a small patient sample size subjected to combination therapy, this study provides novel biomarkers to predict therapy response and suggests potential strategies to overcome immunotherapy resistance.

Background: The superiority of robot-assisted thoracic surgery (RATS) over videoassisted thoracic surgery (VATS) and thoracotomy remains controversial for lung cancer. Methods: A network meta-analysis (NMA) and pairwise meta-analysis (PMA) were performed to evaluate the perioperative outcomes using five databases. Results: Thirty-two studies involving 6593 patients were included for analysis. The NMA showed that RATS had similar operative time, conversion rate to thoracotomy, number of lymph node, postoperative morbidity, and length of hospital stay with VATS, except for lower 30-day mortality. Compared with thoracotomy, longer operative time and shorter hospital stay were observed in RATS, but no significant difference was observed in number of lymph node, postoperative morbidity, and 30-day mortality in both NMA and PMA. In lobectomy/segmentectomy subgroup, all outcomes, except for operative time of RATS vs VATS and number of lymph node, were similar with overall analyses. Conclusions: RATS had comparable perioperative outcomes with VATS and open surgery.