Tonic signaling of chimeric antigen receptor (CAR), i.e., the spontaneous CAR activation in the absence of tumor antigen stimulation, is considered to be a pivotal event controlling CAR-T efficacy. However, the molecular mechanism underlying the spontaneous CAR signals remains elusive. Here, we unveil that positively charged patches (PCPs) on the surface of the CAR antigen-binding domain mediate CAR clustering and result in CAR tonic signaling. For CARs with high tonic signaling (e.g., GD2.CAR and CSPG4.CAR), reducing PCPs on CARs or boosting ionic strength in the culture medium during ex vivo CAR-T cell expansion minimizes spontaneous CAR activation and alleviates CAR-T cell exhaustion. In contrast, introducing PCPs into the CAR with weak tonic signaling, such as CD19.CAR, results in improved in vivo persistence and superior antitumor function. These results demonstrate that CAR tonic signaling is induced and maintained by PCP-mediated CAR clustering. Notably, the mutations we generated to alter the PCPs maintain the antigen-binding affinity and specificity of the CAR. Therefore, our findings suggest that the rational tuning of PCPs to optimize tonic signaling and in vivo fitness of CAR-T cells is a promising design strategy for the next-generation CAR.

Since B7-H3 is overexpressed or amplified in many types of solid tumors with a restricted expression in the normal tissues, it has been an emerging immunotherapeutic target for solid tumors. This review will focus on the structural designs of developing chimeric antigen receptors (CARs) targeting B7-H3. The expression, receptor, and function of the B7-H3, as well as a short overview of B7-H3-targeted monoclonal antibody therapy, are discussed. Finally, a detailed summary of B7-H3 redirected CAR-T and CAR-NK cell approaches utilized in preclinical models and currently ongoing or completed clinical trials are presented. It has been demonstrated that B7-H3-targeted CAR-based cell therapies were safe in initial trials, but their efficacy was limited. Employing the local delivery routes, the introduction of novel modifications promoting CAR-T persistence, and combined treatment with other standard therapies could improve the efficacy of B7-H3-targeted CAR-T cell therapy against solid tumors. Graphical Abstract Cancers develop by avoiding being discovered and destructed by the immune system. Cancer immunotherapy is characterized as an approach to assist the immune system to recognize and fight cancer by using uses some substances. Chimeric antigen receptor (CAR) is a protein designed to recognize a target of interest on tumor cells, immune cells armed with which are able to treat human cancers. B7-H3 is a type I transmembrane protein overexpressed in various solid tumors but scarcely detected in normal tissues. Moreover, it is associated with a poor prognosis for many cancer patients. Therefore, we discussed the role of B7-H3 in solid tumors, and concluded it as a promising therapeutic target for CAR-based immunotherapy. A number of B7-H3 CARs have been developed and tested in recent years, but which CAR construct targeting B7-H3 works best remains uncertain. Up till now, the design of B7-H3 CARs is still controversial and challenging. Hence, we summarized and compared the designs and efficacies of B7-H3 CARs utilized in preclinical models and currently ongoing or completed clinical trials in this review, and aimed to provide a better reference for future B7-H3 CAR design.

Background. Clinically relevant postoperative pancreatic fistula (CR‐POPF) is a severe complication which may be caused by a perioperative nutrition problem. We aimed to study whether patients with high nutritional risk (NRS2002 score ≥ 5) might benefit from preoperative nutrition support regarding the risk of CR‐POPF after open pancreaticoduodenectomy. Methods. Consecutive patients undergoing open pancreaticoduodenectomy with complete record of NRS2002 at two Chinese institutions between 2013 and 2018 were analysed. CR‐POPF was diagnosed following the 2016 ISGPS criteria. Nutrition support included oral nutrition supplement and enteral and parenteral nutrition. Clinical and economic outcomes were analysed. Results. 522 cases were included. 135 cases (25.9%) were at high nutritional risk (NRS2002 score ≥ 5), among which 41 cases (30.4%) received preoperative nutrition support. The CR‐POPF rate was significantly lower in the preoperative nutrition support group compared with the no nutrition support group (12.2% versus 28.7%, P = 0.038). Multivariate analysis showed that preoperative nutrition support was a protective factor for CR‐POPF in patients at high risk [OR 0.339, 95% CI (0.115‐0.965), P = 0.039]. Higher albumin and a larger diameter of the main pancreatic duct were found to be other protectors for CR‐POPF. Conclusions. Patients with high nutritional risk (NRS2002 score ≥ 5) may profit from preoperative nutritional support manifested in the reduction of CR‐POPF.