The transcription factor TFEB is a major regulator of lysosomal biogenesis and autophagy. There is growing evidence that posttranslational modifications play a crucial role in regulating TFEB activity. Here, we show that lactate molecules can covalently modify TFEB, leading to its lactylation and stabilization. Mechanically, lactylation at K91 prevents TFEB from interacting with E3 ubiquitin ligase WWP2, thereby inhibiting TFEB ubiquitination and proteasome degradation, resulting in increased TFEB activity and autophagy flux. Using a specific antibody against lactylated K91, enhanced TFEB lactylation was observed in clinical human pancreatic cancer samples. Our results suggest that lactylation is a novel mode of TFEB regulation and that lactylation of TFEB may be associated with high levels of autophagy in rapidly proliferating cells, such as cancer cells.

Immunotherapeutic interventions represent a promising approach to treating cancer, with strategies such as immune checkpoint blockade (ICB), immunogenic sonodynamic therapy (SDT), and immune adjuvant T cell delivery having exhibited clinical promise. In this report, we describe the use of cancer cell membrane-coated triphenylphosphonium (TPP) decorated nano-metal–organic framework (nMOF) constructs [Zr-TCPP(TPP)/R837@M] that were used to generate homologous, mitochondria-targeted platforms with a high rate of sonosensitizer loading. This construct was utilized to simultaneously promote tumor antigen presentation via enhancing SDT while synergistically promoting dendritic cell (DC) maturation through the delivery of the Toll-like receptor agonist R837. In vitro, these functionalized nMOFs were readily internalized by homologous tumor cells in which they were efficiently targeted to the mitochondria, promoting DC activation through the induction of immunogenic cell death (ICD) following ultrasound exposure. Moreover, this nanoplatform was able to achieve in vivo synergy with anti-CTLA-4 ICB to reverse immunosuppression tumor microenvironment (TME), thus achieving more robust antitumor efficacy capable of suppressing metastatic disease progression and facilitating the development of durable antitumor memory responses. Together, these results highlight a promising approach to achieving enhanced SDT activity while overcoming an immunosuppressive TME, thereby achieving more robust antitumor immunity.