Lactate, a characteristic metabolite of the tumor microenvironment (TME), drives immunosuppression and promotes tumor progression. Material‐engineered strategies for intratumoral lactate modulations demonstrate their promise for tumor immunotherapy. However, understanding of the inherent interconnections of material‐enabled lactate regulation, metabolism, and immunity in the TME is scarce. To address this issue, urchin‐like catalysts of the encapsulated Gd‐doped CeO₂, syrosingopine, and lactate oxidase are used in ZIF‐8 (USL, where U, S, and L represent the urchin‐like Gd‐doped CeO₂@ZIF‐8, syrosingopine, and lactate oxidase, respectively) and orthotopic tumor models. The instructive relationships of intratumoral lactate depletion, metabolic reprogramming, and immune activation for catalytic immunotherapy of tumors is illustrated. The catalysts efficiently oxidize intratumoral lactate and significantly promote tumor cell apoptosis by in situ‐generated ·OH, thereby reducing glucose supply and inducing mitochondrial damage via lactate depletion, thus reprogramming glycometabolism. Subsequently, such catalytic metabolic reprogramming evokes both local and systemic antitumor immunity by activating M1‐polarizaed macrophages and CD8⁺ T cells, leading to potent antitumor immunity. This study provides valuable mechanistic insights into material‐interfered tumor therapy through intratumoral lactate depletion and consequential connection with metabolic reprogramming and immunity remodeling, which is thought to enhance the efficacy of immunotherapy.

Splanchnic vein thrombosis (SVT) is not rare in patients with acute pancreatitis. It remains unclear about whether anticoagulation should be given for acute pancreatitis-associated SVT. The PubMed, EMBASE, and Cochrane Library databases were searched. Rates of SVT recanalization, any bleeding, death, intestinal ischemia, portal cavernoma, and gastroesophageal varices were pooled and compared between patients with acute pancreatitis-associated SVT who received and did not receive therapeutic anticoagulation. Pooled rates and risk ratios (RRs) with 95% confidence intervals (CIs) were calculated. Heterogeneity among studies was evaluated. Overall, 16 studies including 698 patients with acute pancreatitis-associated SVT were eligible. After therapeutic anticoagulation, the pooled rates of SVT recanalization, any bleeding, death, intestinal ischemia, portal cavernoma, and gastroesophageal varices were 44.3% (95%CI = 32.3%-56.6%), 10.7% (95%CI = 4.9%-18.5%), 13.3% (95%CI = 6.9%-21.4%), 16.8% (95%CI = 6.9%-29.9%), 21.2% (95%CI = 7.5%-39.5%), and 29.1% (95%CI = 16.1%-44.1%), respectively. Anticoagulation therapy significantly increased the rate of SVT recanalization (RR = 1.69; 95%CI = 1.29-2.19; P < .01), and marginally increased the risk of bleeding (RR = 1.98; 95%CI = 0.93-4.22; P = .07). The rates of death (RR = 1.42; 95%CI = 0.62-3.25; P = .40), intestinal ischemia (RR = 2.55; 95%CI = 0.23-28.16; P = .45), portal cavernoma (RR = 0.51; 95%CI = 0.21-1.22; P = .13), and gastroesophageal varices (RR = 0.71; 95%CI = 0.38-1.32; P = .28) were not significantly different between patients who received and did not receive anticoagulation therapy. Heterogeneity was statistically significant in the meta-analysis of intestinal ischemia, but not in those of SVT recanalization, any bleeding, death, portal cavernoma, or gastroesophageal varices. Anticoagulation may be effective for recanalization of acute pancreatitis-associated SVT, but cannot improve the survival. Randomized controlled trials are warranted to further investigate the clinical significance of anticoagulation therapy in such patients.

Ca²⁺ plays critical roles in the development of diseases, whereas existing various Ca regulation methods have been greatly restricted in their clinical applications due to their high toxicity and inefficiency. To solve this issue, with the help of Ca overexpressed tumor drug resistance model, the phytic acid (PA)-modified CeO₂ nano-inhibitors have been rationally designed as an unprecedentedly safe and efficient Ca²⁺ inhibitor to successfully reverse tumor drug resistance through Ca²⁺ negative regulation strategy. Using doxorubicin (Dox) as a model chemotherapeutic drug, the Ca²⁺ nano-inhibitors efficiently deprived intracellular excessive free Ca²⁺, suppressed P-glycoprotein (P-gp) expression and significantly enhanced intracellular drug accumulation in Dox-resistant tumor cells. This Ca²⁺ negative regulation strategy improved the intratumoral Dox concentration by a factor of 12.4 and nearly eradicated tumors without obvious adverse effects. Besides, nanocerias as pH-regulated nanozyme greatly alleviated the adverse effects of chemotherapeutic drug on normal cells/organs and substantially improved survivals of mice. We anticipate that this safe and effective Ca²⁺ negative regulation strategy has potentials to conquer the pitfalls of traditional Ca inhibitors, improve therapeutic efficacy of common chemotherapeutic drugs and serves as a facile and effective treatment platform of other Ca²⁺ associated diseases.

To validate the robust predictive values of tumor vascularity and hand-foot-skin reaction (HFSR) in combination treatment of transarterial chemoembolization (TACE) and sorafenib for patients with intermediate hepatocellular carcinoma (HCC), and then select the potential candidates who would survive best from such treatment. A total of 132 treatment-naive patients with intermediate HCC undergoing combination therapy of TACE and sorafenib were recruited between January 2010 and December 2014. The tumor vascularity was defined according to digital subtraction angiography (DSA) and HFSR was assessed by the national cancer institute common terminology criteria for adverse events (NCI-CTCAE). The Mann-Whitney U test was used to assess the correlation between vascularity and radiologic response; time to radiologic progression (TTP) and overall survival (OS) were evaluated using Kaplan-Meier techniques and compared by log-rank test; factors associated with them were evaluated using multivariate Cox regression analysis. During a median follow up of 17.3 months, it was revealed that hypervascularity and development of ≥2 grade of HFSR within 60 days after sorafenib initiation were favorable predictors for TTP (HR 0.378, p < 0.001; HR 0.627, p = 0.018) and OS (HR 0.499, p = 0.002; HR 0.555, p = 0.004). The median TTP and OS for patients with both were 12.2 and 29.1 months, which were better than patients with either of them (6.0 months, HR 1.74, p = 0.012; 16.5 months, HR 1.73, p = 0.021), as well as those with neither (2.9 months, HR 3.74, p < 0.001; 11.9 months, HR 3.17, p < 0.001). Tumor hypervascularity and development of ≥2 grade of HFSR within 60 days were favorable predictive factors for the combination treatment of TACE and sorafenib, with both of which the patients survived longest and might be the potential candidates.

During the process of liver fibrosis, hepatic stellate cells (HSCs) play a critical role in the excessive production of extracellular matrix (ECM). Previous studies have indicated that the monomer IH764-3, one of the major bioactive components of Salvia miltiorrhiza, is able to inhibit HSC proliferation and induce the apoptosis of activated HSCs in vitro. In the current study, we used a rat model of liver fibrosis induced by bile duct ligation (BDL) to investigate the effect of the monomer IH764-3 on the induction of apoptosis in HSCs in vivo. The rat model of liver fibrosis was established by BDL. Immunohistochemical staining of α-smooth muscle actin (α-SMA) was performed to detect HSC activation and proliferation and HSC apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and α-SMA immunohistochemical double staining. In addition, the protein expression levels of focal adhesion kinase (FAK), p-FAK (Tyr397), extracellular signal-regulated kinase (ERK) and p-ERK and the mRNA expression levels of FAK and ERK were measured by western blotting and reverse transcription-polymerase chain reaction (RT-PCR), respectively. The monomer IH764-3 was associated with a significant decrease in intrahepatic fibrogenesis and collagen deposition and attenuated the liver fibrosis induced by BDL. Immunohistochemical staining revealed that the expression of α-SMA in the IH764-3 group was significantly decreased compared with that in the model group (12.92±2.45 vs. 22.65±2.16%, P<0.01). TUNEL and α-SMA immunohistochemical double staining also confirmed that IH764-3 increased the apoptotic rate of the activated HSCs (34.8±4.5 vs. 4.72±0.37%, P<0.01). Moreover, the results revealed that IH764-3 downregulated the expression levels of FAK, p-FAK (Tyr397), ERK and p-ERK in the liver tissue of rats with liver fibrosis. The monomer IH764-3 ameliorates experimental liver fibrosis by inhibiting HSC proliferation and inducing HSC apoptosis, warranting its use as a potential therapeutic agent in the treatment of liver fibrosis.

Background: The non-negligible role of epigenetic modifications in cancer development and tumor microenvironment (TME) has been demonstrated in recent studies. Nonetheless, the potential regulatory role of N7-methylguanosine (m⁷G) modification in shaping and impacting the TME remains unclear.Methods: A comprehensive analysis was performed to explore the m⁷G modification patterns based on 24 potential m⁷G regulators in 817 lung adenocarcinoma (LUAD) patients, and the TME landscape in distinct m⁷G modification patterns were evaluated. The m⁷G score was established based on principal component analysis (PCA) to quantify m⁷G modification patterns and evaluate the TME cell infiltrating characteristics of individual tumors. Further, correlation analyses of m7Gscore with response to chemotherapy and immunotherapy were performed.Results: We identified three distinct m⁷G modification patterns with the biological pathway enrichment and TME cell infiltrating characteristics corresponded to immune-desert, immune-inflamed and immune-excluded phenotype, respectively. We further demonstrated the m⁷Gscore could predict the TME infiltrating characteristics, tumor mutation burden (TMB), response to immunotherapy and chemotherapy, as well as prognosis of individual tumors. High m⁷Gscore was associated with increased component of immune cell infiltration, low TMB and survival advantage, while low m⁷Gscore was linked to decreased immune cell infiltration and increased TMB. Additionally, patients with lower m⁷Gscore demonstrated significant therapeutic advantages.Conclusion: This study demonstrated the regulatory mechanisms of m⁷G modification on TME formation and regulation of lung adenocarcinoma. Identification of individual tumor m⁷G modification patterns will contribute to the understanding of TME characterization and guiding more effective immunotherapy strategies.