Hepatocellular carcinoma (HCC) contains a subset of cancer stem cells (CSC) that cause tumor recurrence, metastasis, and chemical resistance. Histone deacetylase 11 (HDAC11) mediates diverse immune functions and metabolism, yet little is known about its role in HCC CSCs. In this study, we report that HDAC11 is highly expressed in HCC and is closely related to disease prognosis. Depletion of HDAC11 in a conditional knockout mouse model reduced hepatocellular tumorigenesis and prolonged survival. Loss of HDAC11 increased transcription of LKB1 by promoting histone acetylation in its promoter region, thereby activating the AMPK signaling pathway and inhibiting the glycolysis pathway, which in turn leads to the suppression of cancer stemness and HCC progression. Furthermore, HDAC11 overexpression reduced HCC sensitivity to sorafenib. Collectively, these data propose HDAC11 as a new target for combination therapy in patients with kinase-resistant HCC.Significance: This study finds that HDAC11 suppresses LKB1 expression in HCC to promote cancer stemness, progression, and sorafenib resistance, suggesting the potential of targeting HDAC11 to treat HCC and overcome kinase inhibitor resistance.

As nanoscale extracellular vesicles, exosomes are secreted by various cell types, and they are widely distributed in multiple biological fluids. Studies have shown that tumor-derived exosomes can carry a variety of primary tumor-specific molecules, which may represent a novel tool for the early detection of cancer. However, the clinical translation of exosomes remains a challenge due to the requirement of large quantities of samples when enriching the cancer-related exosomes in biological fluids, the insufficiency of traditional techniques for exosome subpopulations, and the complex exosome isolation of the current commercially available exosome phenotype profiling approaches. The evolving surface-enhanced Raman scattering (SERS) technology, with properties of unique optoelectronics, easy functionalization, and the particular interaction between light and nanoscale metallic materials, can achieve sensitive detection of exosomes without large quantities of samples and multiplexed phenotype profiling, providing a new mode of real-time and noninvasive analysis for cancer patients. In the present review, we mainly discussed exosome detection based on SERS, especially SERS immunoassay. The basic structure and function of exosomes were firstly introduced. Then, recent studies using the SERS technique for cancer detection were critically reviewed, which mainly included various SERS substrates, biological modification of SERS substrates, SERS-based exosome detection, and the combination of SERS and other technologies for cancer diagnosis. This review systematically discussed the essential aspects, limitations, and considerations of applying SERS technology in the detection and analysis of cancer-derived exosomes, which could provide a valuable reference for the early diagnosis of cancer through SERS technology. STATEMENT OF SIGNIFICANCE: Surface-enhanced Raman scattering (SERS) has been applied to exosomes detection to obtain better diagnostic results. In past three years, several reviews have been published in exosome detection, which were narrowly focus on methods of exosome detection. Selection and surface functionalization of the substrate and the combination detection with different methods based on SERS will provide new strategies for the detection of exosomes. This review will focus on the above aspects. This emerging detection method is constantly evolving and contributing to the early discovery of diseases in the future.

Exploiting cancer metabolism for the clinical benefit of patients with hepatocellular carcinoma (HCC) is a topic under active investigation. Ubiquitin-specific peptidase 48 (USP48), a member of the ubiquitin-specific protease family, is involved in tumor growth, inflammation, and genome stability. However, the role of USP48 in HCC tumorigenesis remains unknown. In this study, we report that expression of USP48 is downregulated in diethylnitrosamine-induced liver tumorigenesis in mice as well as in human HCC. USP48 physically bound and stabilized SIRT6 by K48-linked deubiquitination at the K33 and K128 sites of SIRT6, which impeded metabolic reprogramming to hamper HCC tumorigenesis. Moreover, methyltransferase-like 14 (Mettl14)–induced m6A modification participated in the regulation of USP48 in HCC by maintaining USP48 mRNA stability. Our work uncovers the tumor-suppressive function of the Mettl14–USP48–SIRT6 axis via modulation of glycolysis, providing new insights into the critical roles of metabolic activities in HCC and identifying an attractive target for future treatment studies. Significance: These findings demonstrate that USP48 is regulated by Mettl14-induced m6A modification and stabilizes SIRT6 to attenuate HCC glycolysis and malignancy.

Hypoxia is a common phenomenon in most malignant tumors, especially in pancreatic cancer (PC). Hypoxia is the result of unlimited tumor growth and plays an active role in promoting tumor survival, progression, and invasion. As the part of the hypoxia microenvironment in PC is gradually clarified, hypoxia is becoming a key determinant and an important therapeutic target of pancreatic cancer. To adapt to the severe hypoxia environment, cells have changed their metabolic phenotypes to maintain their survival and proliferation. Enhanced glycolysis is the most prominent feature of cancer cells' metabolic reprogramming in response to hypoxia. It provides the energy source for hypoxic cancer cells (although it provides less than oxidative phosphorylation) and produces metabolites that can be absorbed and utilized by normoxic cancer cells. In addition, the uptake of glutamine and fatty acids by hypoxic cancer cells is also increased, which is also conducive to tumor progression. Their metabolites are pooled in the hexosamine biosynthesis pathway (HBP). As a nutrition sensor, HBP, in turn, can coordinate glucose and glutamine metabolism. Its end product, UDP-GlcNAc, is the substrate of protein post-translational modification (PTM) involved in various signaling pathways supporting tumor progression. Adaptive metabolic changes of cancer cells promote their survival and affect tumor immune cells in the tumor microenvironment (TME), which contributes to tumor immunosuppressive microenvironment and induces tumor immunotherapy resistance. Here, we summarize the hypoxic microenvironment, its effect on metabolic reprogramming, and its contribution to immunotherapy resistance in pancreatic cancer.

Pyroptosis is a type of programmed cell death characterized by the activation of inflammatory caspases and the cleavage of gasdermin proteins. Pyroptosis can suppress tumor development and induce antitumor immunity, and activating pyroptosis is a potential treatment strategy for cancer. To uncover approaches to harness the anticancer effects of pyroptosis, we aimed to identify regulators of pyroptosis in cancer. A CRISPR-Cas9 screen identified that loss of USP48, a deubiquitinating enzyme, significantly inhibited cell pyroptosis. USP48 promoted pyroptosis by stabilizing gasdermin E (GSDME). USP48 bound GSDME and removed K48-linked ubiquitination at positions K120 and K189. Clinical tissue testing confirmed that the expression of USP48 positively correlated with GSDME and pyroptosis-related factors. Single-cell sequencing showed that the functions of T cells and tumor-associated macrophages in the tumor microenvironment were inhibited after USP48 knockout. Finally, overexpression of USP48 enhanced the therapeutic efficacy of programmed cell death protein 1 inhibitors in tumors in mouse models. Together, these findings define a pyroptosis regulation pathway and indicate that pharmacologic activation of USP48 may provide an effective strategy to sensitize cancer cells to pyroptosis and improve response to immunotherapy. Significance: USP48 promotes pyroptosis by deubiquitinating GSDME and enhances antitumor immunity, indicating that increasing USP48 activity may be a future therapeutic strategy for treating cancer.

Lysine lactylation (Kla) plays a vital role in several physiological processes. However, the cancer‐specific modulation of Kla in gastrointestinal (GI) tumors requires systematic elucidation. Here, global lactylome profiling of cancerous and adjacent tissues is conducted from 40 patients with GI cancer and identified 11698 Kla sites. Lactylome integration revealed that Kla affects proteins involved in hallmark cancer processes, including epigenetic rewiring, metabolic perturbations, and genome instability. Moreover, the study revealed pan‐cancer patterns of Kla alterations, among which 37 Kla sites are consistently upregulated in all four GI cancers and are involved in gene regulation. It is further verified that lactylation of CBX3 at K10 mediates its interaction of CBX3 with the epigenetic marker H3K9me3 and facilitates GI cancer progression. Overall, this study provides an invaluable resource for understanding the lactylome landscape in GI cancers, which may provide new paths for drug discovery for these devastating diseases.