Anticancer drug‐loaded nanoparticles have been explored extensively to decrease side effects while improving their therapeutic efficacy. However, due to the low drug loading content, premature drug release, nonstandardized carrier structure, and difficulty in predicting the fate of the carrier, only a few nanomedicines have been approved for clincial use. Herein, a carrier‐free nanoparticle based on the self‐assembly of the curcumin–erlotinib conjugate (EPC) is developed. The EPC nanoassembly exhibits more potent cell killing, better antimigration, and anti‐invasion effects for BxPC‐3 pancreatic cancer cells than the combination of free curcumin and erlotinib. Furthermore, benefiting from both passive and active tumor targeting effect, EPC nanoassembly can effectively accumulate in the tumor tissue in a xenograft pancreatic tumor mouse model. Consequently, EPC effectively reduces the growth of pancreatic tumors and extends the median survival time of the tumor‐bearing mice from 22 to 68 days. In addition, no systemic toxicity is detected in the mice receiving EPC treatment. Attributed to the uniformity of the curcumin–erlotinib conjugate and easiness of scaling up, it is expected that the EPC can be translated into a powerful tool in fighting against pancreatic cancer and other epidermal growth factor receptor positive cancers.

ESCC is a highly malignant tumor, and its morbidity and mortality in China account for more than 50% of the world’s total rates. As effective treatments are lacking, the 5-year survival rate of patients does not exceed 30%. CAR-T-cell-based immunotherapy has emerged as one of the most promising cancer treatments; however, there are relatively fewer reports regarding its application for ESCC. In this study, we conducted large-sample whole-genome sequencing (WGS) and RNA-seq analysis of patients with ESCC from China to examine the feasibility of EGFR-targeting CAR-T cells in the treatment of ESCC. We found much higher levels of EGFR gene amplification and overexpression in tumors than in the normal tissues, indicating that EGFR could be a promising target of CAR-T-cell-based immunotherapy in ESCC. Therefore, we tested EGFR-targeting CAR-T cells for lytic activity against ESCC cells as a model to establish cellular immunotherapy for ESCC. Five types of CAR-T cells targeting EGFR were constructed, two of which, CAR1-T and CAR2-T, showed a strong cytotoxicity against ESCC in in vitro and in vivo experiments. The results of this study suggest that CAR1-T and CAR2-T have the potential to be used for anti-ESCC immunotherapy in clinics.

N6-methyladenosine (m ⁶ A) represents the most abundant mRNA modification, yet its role in natural killer (NK) cell development remains incompletely understood. Here we demonstrate that the m ⁶ A methyltransferase METTL14 plays an indispensable, stage-specific role in early NK cell development. Mettl14 deficiency at the progenitor stage caused severe NK cell lymphopenia by disrupting the NK progenitor to immature NK cell transition. Paradoxically, residual Mettl14 -null NK cells exhibited a hypermetabolic state characterized by mTORC1 hyperactivation and enhanced mitochondrial function, which drove both hyperproliferation and activation-induced cell death via p53 and apoptotic pathway activation. Despite developmental defects, these cells demonstrated superior capacity to control melanoma metastasis in vivo. Mechanistically, METTL14 fine-tuned IL-15 responsiveness likely by sustaining SOCS3 expression to restrain JAK-STAT5 signaling. Terminal deletion of Mettl14 produced no phenotype, underscoring its specific requirement during early development. Our findings establish METTL14 as a crucial checkpoint coordinating transcriptional and metabolic programs to ensure NK cell homeostasis.