Regulatory T cells (Tregs) are essential to the negative regulation of the immune system, as they avoid excessive inflammation and mediate tumor development. The abundance of Tregs in tumor tissues suggests that Tregs may be eliminated or functionally inhibited to stimulate antitumor immunity. However, immunotherapy targeting Tregs has been severely hampered by autoimmune diseases due to the systemic elimination of Tregs. Recently, emerging studies have shown that metabolic regulation can specifically target tumor-infiltrating immune cells, and lipid accumulation in TME is associated with immunosuppression. Nevertheless, how Tregs actively regulate metabolic reprogramming to outcompete effector T cells (Teffs), and how lipid metabolic reprogramming contributes to the immunomodulatory capacity of Tregs have not been fully discussed. This review will discuss the physiological processes by which lipid accumulation confers a metabolic advantage to tumor-infiltrating Tregs (TI-Tregs) and amplifies their immunosuppressive functions. Furthermore, we will provide a summary of the driving effects of various metabolic regulators on the metabolic reprogramming of Tregs. Finally, we propose that targeting the lipid metabolism of TI-Tregs could be efficacious either alone or in conjunction with immune checkpoint therapy.

Gallbladder cancer (GBC) is a rare but the most malignant type of biliary tract tumor. It is usually diagnosed at an advanced stage and conventional treatments are unsatisfactory. As a proteasome inhibitor, bortezomib (BTZ) exhibits excellent antitumor ability in GBC. However, the long‐term treatment efficacy is limited by its resistance, poor stability, and high toxicity. Herein, BTZ‐encapsulated pH‐responsive copolymeric nanoparticles with estrone (ES‐NP_{(BTZ; Ce6)}) for GBC‐specific targeted therapy is reported. Due to the high estrogen receptor expression in GBC, ES‐NP_{(BTZ; Ce6)} can rapidly enter the cells and accumulate near the nucleus via ES‐mediated endocytosis. Under acidic tumor microenvironment (TME) and 808 nm laser irradiation, BTZ is released and ROS is generated by Ce6 to destroy the “bounce‐back” response pathway proteins, such as DDI2 and p97, which can effectively inhibit proteasomes and increase apoptosis. Compared to the traditional treatment using BTZ monotherapy, ES‐NP_{(BTZ; Ce6)} can significantly impede disease progression at lower BTZ concentrations and improve its resistance. Moreover, ES‐NP_{(BTZ; Ce6)} demonstrates similar antitumor abilities in patient‐derived xenograft animal models and five other types of solid tumor cells, revealing its potential as a broad‐spectrum antitumor formulation.

Objectives: The objective of our project is to explore a noninvasive radiomics model based on magnetic resonance imaging (MRI) that could recognize the expression of vascular endothelial growth factor (VEGF) in hepatocellular carcinoma before operation.Methods: 202 patients with proven single HCC were enlisted and stochastically distributed into a training set (n = 142) and a test set (n = 60). Arterial phase, portal venous phase, balanced phase, delayed phase, and hepatobiliary phase images were used to radiomics features extraction. We retrieved 1906 radiomic features from each phase of every participant’s MRI images. The F-test was applied to choose the crucial features. A logistic regression model was adopted to generate a radiomics signature. By combining independent risk indicators from the fusion radiomics signature and clinico-radiological features, we developed a multivariable logistic regression model that could predict the VEGF status preoperatively through calculating the area under the curve (AUC).Results: The entire group comprised 108 VEGF-positive individuals and 94 VEGF-negative patients. AUCs of 0.892 (95% confidence interval [CI]: 0.839 - 0.945) in the training dataset and 0.800 (95% CI: 0.682 - 0.918) in the test dataset were achieved by utilizing radiomics features from two phase images (8 features from the portal venous phase and 5 features from the hepatobiliary phase). Furthermore, the nomogram relying on a combined model that included the clinical factors α-fetoprotein (AFP), irregular tumor margin, and the fusion radiomics signature performed well in both the training (AUC = 0.936, 95% CI: 0.898-0.974) and test (AUC = 0.836, 95% CI: 0.728-0.944) datasets.Conclusions: The combined model acquired from two phase (portal venous and hepatobiliary phase) pictures of gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI could be considered as a credible prognostic marker for the level of VEGF in HCC.

Aim: To determine if PD-L1 can be used as a biomarker to predict the efficacy of anti-PD-1/PD-L1 inhibitors in hepatocellular carcinoma (HCC). Methods: Relevant studies from a specific search of th... Plain language summary Clinically, liver cancer patients with high PD-L1 levels may not benefit from immunotherapy. Conversely, some patients with low PD-L1 level can benefit from it. Therefore, th...

Background: Penfluridol (PF) is an FDA-approved antipsychotic drug that has recently been shown to have anticancer activity. However, the anticancer effects and underlying mechanisms of PF are not well-established in gallbladder cancer (GBC). Methods: The anticancer efficacy of PF on GBC was investigated via a series of cell functions experiments, including cell viability, colony formation, apoptosis assays, and so on. The corresponding signaling changes after PF treatment were explored by western blotting. Then, nude mice were utilized to study and test the anticancer activity of PF in vivo. Besides, glucose consumption and lactic production assays were used to detect the glycolysis alteration. Results: In this study, we discovered that PF greatly inhibited the proliferation and invasion ability of GBC cells (GBCs). The glucose consumption and lactic generation ability of GBCs were dramatically elevated following PF treatment. Additionally, we discovered that inhibiting glycolysis could improve PF's anticancer efficacy. Further studies established that the activation of the AMPK/PFKFB3 signaling pathway medicated glycolysis after PF treatment. We proved mechanistically that inhibition of AMPK/PFKFB3 singling pathway mediated glycolysis was a potential synergetic strategy to improve the anticancer efficacy of PF on GBC. Conclusions: By inhibiting AMPK, the anticancer effects of PF on GBCs were amplified. As a result, our investigations shed new light on the possibility of repurposing PF as an anticancer drug for GBC, and AMPK inhibition in combination with PF may represent a novel therapeutic strategy for GBC. Graphical