Tumor cells balance ATP production and carbon skeleton synthesis by flexibly altering catabolic pathways to sustain their significant growth advantage. Uncouplers have shown potential for tumor suppression by converting chemical energy from catabolism into heat. However, their use may be limited due to indiscriminate metabolic interference in both tumor and normal cells, as well as the uncertainty surrounding their effects on the immune microenvironment. Herein, we found that low-dose uncoupler BAM15 promoted AMPK, AKT signaling, and the TCA cycle without increasing cell proliferation or inducing cell death in vitro, suggesting an increase in futile cycling. Intratumoral injection of 50 ng/mL BAM15 accelerated catabolic processes while inhibiting anabolic pathways, resulting in a metabolomic reshaping with increased levels of linoleic acid, C5DC, and others. These changes were shown to enhance tumor-killing effects by T cells. To reduce side effects on normal tissues and improve tumor retention, BAM15 was targeted for delivery by loading it into TCVs. This TCV-BAM15 treatment significantly increased CD8+ T cell counts and granzyme B levels. Our findings highlight a previously unrecognized therapeutic effect and signaling mechanism of low-dose BAM15 treatment in tumors. We propose that this novel strategy holds promise as a tumor immunity therapy with fewer adverse effects compared to free uncoupling drugs at high concentrations.
Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic liver disease closely related to obesity, which has become a global health problem. However, current pharmacological therapies for NAFLD are limited by potential side effects, low effectiveness and poor aqueous solubility. Herein, we designed functionalized drug-albumin nanocomposites ( [email protected] NPs), which were prepared by self-assembly of the anti-obesity small-molecule drug (BAM15) and bovine serum albumin (BSA), for treatment of NAFLD. The proposed [email protected] NPs not only improve aqueous solubility and half-life of BAM15 but also exhibit hepatic-targeted capacity and an increased therapeutic efficacy. In vitro experiments revealed that [email protected] NPs possessed excellent biocompatibility, and improved resistance to adipogenesis and reduced lipid accumulation in human hepatocellular carcinoma cells. In vivo , [email protected] NPs showed liver targeting ability and powerful anti-obesity effects without altering body temperature or affecting food intake, and could effectively alleviate hepatic steatosis and improve therapeutic efficacy for NAFLD treatment. The above findings demonstrated that [email protected] NPs potentially served as a safe and effective drug for NAFLD treatment.
危险品化学品经营许可证（带存储）