The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically^1,2. This results in substantial accumulation of lacate, the end product of anaerobic glycolysis, in cancer cells³. However, how cancer metabolism affects chemotherapy response and DNA repair in general remains incompletely understood. Here we report that lactate-driven lactylation of NBS1 promotes homologous recombination (HR)-mediated DNA repair. Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11–RAD50–NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks. Furthermore, we identify TIP60 as the NBS1 lysine lactyltransferase and the ‘writer’ of NBS1 K388 lactylation, and HDAC3 as the NBS1 de-lactylase. High levels of NBS1 K388 lactylation predict poor patient outcome of neoadjuvant chemotherapy, and lactate reduction using either genetic depletion of lactate dehydrogenase A (LDHA) or stiripentol, a lactate dehydrogenase A inhibitor used clinically for anti-epileptic treatment, inhibited NBS1 K388 lactylation, decreased DNA repair efficacy and overcame resistance to chemotherapy. In summary, our work identifies NBS1 lactylation as a critical mechanism for genome stability that contributes to chemotherapy resistance and identifies inhibition of lactate production as a promising therapeutic cancer strategy.

The atrial natriuretic peptide (ANP), a cardiovascular hormone, plays a pivotal role in the homeostatic control of blood pressure, electrolytes, and water balance and is approved to treat congestive heart failure. In addition, there is a growing realization that ANPs might be related to immune response and tumor growth. The anti-inflammatory and immune-modulatory effects of ANPs in the tissue microenvironment are mediated through autocrine or paracrine mechanisms, which further suppress tumorigenesis. In cancers, ANPs show anti-proliferative effects through several molecular pathways. Furthermore, ANPs attenuate the side effects of cancer therapy. Therefore, ANPs act on several hallmarks of cancer, such as inflammation, angiogenesis, sustained tumor growth, and metastasis. In this review, we summarized the contributions of ANPs in diverse aspects of the immune system and the molecular mechanisms underlying the anti-cancer effects of ANPs.

Objective: To investigate the potential of prophylactic closure of mucosal defects to prevent adverse events following endoscopic resection of superficial layers of the gastrointestinal (GI) wall.Design: Systematic review and meta-analysis.Data sources: We searched PubMed, Embase, Web of Science and the Cochrane Library for studies eligible for inclusion in our meta-analysis from inception to February 2022.Data extraction and synthesis: We compared the effects of closure versus non-closure of mucosal defects with respect to adverse events including delayed bleeding, delayed perforation and postpolypectomy coagulation syndrome (PPCS). We used a random-effects model for all analyses. Subgroup analyses were performed based on gastrointestinal sites, surgical procedures and study designs.Results: In total, this study includes 11 383 patients from 28 studies. For delayed bleeding, closure group was associated with a lower incidence (Risk Ratio [RR]: 0.40, 95% Confidence interval [CI]: 0.30 to 0.53, p<0.001; I²=25%) and consistent results were observed in the subgroups. Also, for delayed perforation, a combined analysis of all sites and surgical methods showed a protective effect of prophylactic closure of mucosal defects (RR: 0.42, 95% CI: 0.22 to 0.82, p=0.01; I²=0%). Similar results were observed in the subgroup analyses, despite the wide CIs. Regarding the PPCS, neither the pooled RRsnor the subgroup analyses showed significant differences.Conclusion: Prophylactic closure of mucosal defects is beneficial in reducing the incidence of delayed bleeding and delayed perforation after endoscopic resection, but there is no significant difference in reducing the incidence of PPCS.

Chemotherapy-associated metastasis is a major cause of failure of cancer treatment, especially neoadjuvant chemotherapy. Extracellular matrix (ECM) remodeling aways accompany with chemotherapy, but its role in chemotherapy-associated metastasis is still unclear. Here, we reveal hyaluronidase-driven degradation of hyaluronic acid (HA) as a key mechanism underlying chemotherapy-associated lymphatic metastasis in gastric cancer. We found that chemotherapy-associated lymphatic metastasis of gastric cancer occurred during neoadjuvant chemotherapy in both patients and nude mice. The proportion of HA increased significantly in ECM during chemotherapy. We also found that cell migration inducing hyaluronidase 2 (CEMIP2) is the most highly expressed hyaluronidase to degrade HA into its effective type, low molecular weight HA (LMWHA), and promoted chemotherapy-associated lymphatic metastasis of gastric cancer. Mechanistically, CEMIP2-generated LMWHA activates CD44-ATF3 signaling to transcriptionally upregulate TGFβ receptor TGFBR1, driving metastasis. CEMIP2 is highly expressed in gastric epithelium naturally. To specifically target CEMIP2 and inhibit chemotherapy-associated lymphatic metastasis of gastric cancer, we developed bioengineered RGD-conjugated exosomes mimics (EMs) for targeted delivery of CEMIP2 siRNA. This strategy potently suppressed chemotherapy-associated lymphatic metastasis in vivo. Crucially, our results position CEMIP2 as a therapeutic target to inhibit chemotherapy-associated metastasis of gastric cancer.