Efficacy and safety of neoadjuvant immunotherapy plus chemotherapy followed by adjuvant immunotherapy in resectable non-small cell lung cancer: a meta-analysis of phase 3 clinical trials.

Objective: At present, several important trials have been published show that perioperative immunotherapy combined with chemotherapy can improve the prognosis of patients with resectable non-small cell lung cancer, which further optimizes treatment options. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of perioperative immunotherapy combined with chemotherapy in resectable non-small cell lung cancer. Methods: The following databases were searched for relevant studies: PubMed, EMBASE, Cochrane library (updated 12 October 2023). All randomized trials comparing perioperative immunotherapy combined with chemotherapy versus chemotherapy alone in resectable non-small cell lung cancer were eligible for inclusion. Data were analyzed using Review Manager 5.4.1 (Cochrane collaboration software). Primary outcomes and measures included overall survival (OS), event-free survival (EFS), pathological complete response (pCR), major pathological response (MPR), R0 resection rate, rate of underwent surgery and adverse events (AEs). Results: A total of 2912 patients (1453 receiving perioperative immunotherapy plus chemotherapy and 1459 receiving chemotherapy alone) were included in this systematic review and meta-analysis. The result showed that compared with chemotherapy alone, combined therapy significantly improved OS (HR = 0.68;95% CI: 0.56-0.83), EFS (HR = 0.58;95% CI: 0.51-0.65), pCR (OR = 7.53;95% CI: 4.63-12.26), MPR (OR = 5.03;95% CI: 3.40-7.44), R0 resection (OR = 1.58;95% CI: 1.152.18) and rate of underwent surgery (OR = 1.25;95% CI: 1.04-1.49). However, combination therapy was associated with higher risk of severe adverse event (OR = 1.46;95% CI: 1.19-1.78; P=0.0002), grade 3 and higher treatment-related adverse event (TRAE) (OR = 1.25;95% CI: 1.06-1.49; P=0.010), TRAE that led to interruption (OR = 1.90;95% CI: 1.34-2.68; P=0.0003) and immune-related adverse event (OR = 2.78;95% CI: 2.18-3.55; P<0.00001). Significant benefits were observed across most subgroups of EFS and pCR. However, no statistical differences were observed for EFS of never smoked (HR = 0.73;95% CI: 0.51-1.05) and EGFR-mutation positive (HR = 0.35;95% CI: 0.04-3.03). Conclusion: This systematic review and meta-analysis found superior efficacy associated with perioperative immunotherapy plus chemotherapy compared with chemotherapy alone in both tumor regression and prolonged survival in resectable NSCLC, but increased the risk of TRAE, so monitoring for adverse events is warranted. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier (CRD42023476786).

Berberine-based self-assembly agents with enhanced synergistic antitumor efficacy.

Tumors are still a major threat to people worldwide. Nanodrug delivery and targeting systems can significantly improve the therapeutic efficacy of chemotherapeutic drugs for antitumor purposes. However, many nanocarriers are likely to exhibit drawbacks such as a complex preparation process, limited drug-loading capacity, untargeted drug release, and toxicity associated with nanocarriers. Therefore, new therapeutic alternatives are urgently needed to develop antitumor drugs. Natural products with abundant scaffold diversity and structural complexity, which are derived from medicinal plants, are important sources of new antitumor drugs. Here, two carrier-free berberine (BBR)-based nanoparticles (NPs) were established to increase the synergistic efficacy of tumor treatment. BBR can interact with glycyrrhetinic acid (GA) and artesunate (ART) to self-assemble BBR-GA and BBR-ART NPs without any nanocarriers, respectively, the formation of which is dominated by electrostatic and hydrophobic interactions. Moreover, BBR-GA NPs could lead to mitochondria-mediated cell apoptosis by regulating mitochondrial fission and dysfunction, while BBR-ART NPs induced ferroptosis in tumor cells. BBR-based NPs have been demonstrated to possess significant tumor targeting and enhanced antitumor properties compared with those of simple monomer mixes both in vitro and in vivo. These carrier-free self-assemblies based on natural products provide a strategy for synergistic drug delivery and thus offer broad prospects for developing enhanced antitumor drugs.

Target Separation and Potential Anticancer Activity of Withanolide-Based Glucose Transporter Protein 1 Inhibitors from Physalis angulata var. villosa.

The glucose transporter 1 (GLUT1) protein is involved in the basal-level absorption of glucose in tumor cells. Inhibiting GLUT1 decreases tumor cell proliferation and induces tumor cell damage. Natural GLUT1 inhibitors have been studied only to a small extent, and the structures of known natural GLUT1 inhibitors are limited to a few classes of natural products. Therefore, discovering and researching other natural GLUT1 inhibitors with novel scaffolds are essential. Physalis angulata L. var. villosa is a plant known as Mao-Ku-Zhi (MKZ). Withanolides are the main phytochemical components of MKZ. MKZ extracts and the components of MKZ exhibited antitumor activity in recent pharmacological studies. However, the antitumor-active components of MKZ and their molecular mechanisms remain unknown. A cell membrane-biomimetic nanoplatform (CM@Fe3O4/MIL-101) was used for target separation of potential GLUT1 inhibitors from MKZ. A new withanolide, physagulide Y (2), together with six known withanolides (1, 3-7), was identified as a potential GLUT1 inhibitor. Physagulide Y was the most potent GLUT1 inhibitor, and its antitumor activity and possible mechanism of action were explored in MCF-7 human cancer cells. These findings advance the development of technologies for the targeted separation of natural products and identify a new molecular framework for the investigation of natural GLUT1 inhibitors.

PROTAC Nanoplatform with Targeted Degradation of NAD(P)H:Quinone Oxidoreductase 1 to Enhance Reactive Oxygen Species-Mediated Apoptosis.

Apoptosis mediated by reactive oxygen species (ROS) has emerged as a promising therapeutic strategy for tumors. However, the overexpression of NAD(P)H:quinone oxidoreductase 1 (NQO1) protein restricted ROS production through a negative feedback pathway in tumor cells, promoting tumor progression, and weakening the effect of drug therapy. Here, a PROTACs nanodrug delivery system (PN) was constructed to increase ROS generation by degrading the NQO1 protein. Specifically, a PROTAC (proteolytic targeting chimera) molecule DQ was designed and synthesized. Then DQ and withaferin A (WA, an inducer of ROS) were loaded into PNs. DQ degraded the overexpressed NQO1 protein in tumor cells through a protein ubiquitination degradation pathway, thereby weakening the antioxidant capacity of tumor cells. Meanwhile, the reduction of NQO1 could inhibit the negative feedback effect of ROS production, thus increasing ROS generation. It has been demonstrated that PNs can significantly increase ROS production and possess potent antitumor properties in vitro and in vivo. This nanoplatform may offer an alternative approach to treating tumors with NQO1 overexpression.