The lactate receptor HCAR1 drives the recruitment of immunosuppressive PMN-MDSCs in colorectal cancer
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Targeting of TAMs: can we be more clever than cancer cells?
With increasing incidence and geography, cancer is one of the leading causes of death, reduced quality of life and disability worldwide. Principal progress in the development of new anticancer therapies, in improving the efficiency of immunotherapeutic tools, and in the personification of conventional therapies needs to consider cancer-specific and patient-specific programming of innate immunity. Intratumoral TAMs and their precursors, resident macrophages and monocytes, are principal regulators of tumor progression and therapy resistance. Our review summarizes the accumulated evidence for the subpopulations of TAMs and their increasing number of biomarkers, indicating their predictive value for the clinical parameters of carcinogenesis and therapy resistance, with a focus on solid cancers of non-infectious etiology. We present the state-of-the-art knowledge about the tumor-supporting functions of TAMs at all stages of tumor progression and highlight biomarkers, recently identified by single-cell and spatial analytical methods, that discriminate between tumor-promoting and tumor-inhibiting TAMs, where both subtypes express a combination of prototype M1 and M2 genes. Our review focuses on novel mechanisms involved in the crosstalk among epigenetic, signaling, transcriptional and metabolic pathways in TAMs. Particular attention has been given to the recently identified link between cancer cell metabolism and the epigenetic programming of TAMs by histone lactylation, which can be responsible for the unlimited protumoral programming of TAMs. Finally, we explain how TAMs interfere with currently used anticancer therapeutics and summarize the most advanced data from clinical trials, which we divide into four categories: inhibition of TAM survival and differentiation, inhibition of monocyte/TAM recruitment into tumors, functional reprogramming of TAMs, and genetic enhancement of macrophages.
Neutrophils in cancer: from biology to therapy
The view of neutrophils has shifted from simple phagocytic cells, whose main function is to kill pathogens, to very complex cells that are also involved in immune regulation and tissue repair. These cells are essential for maintaining and regaining tissue homeostasis. Neutrophils can be viewed as double-edged swords in a range of situations. The potent killing machinery necessary for immune responses to pathogens can easily lead to collateral damage to host tissues when inappropriately controlled. Furthermore, some subtypes of neutrophils are potent pathogen killers, whereas others are immunosuppressive or can aid in tissue healing. Finally, in tumor immunology, many examples of both protumorigenic and antitumorigenic properties of neutrophils have been described. This has important consequences for cancer therapy, as targeting neutrophils can lead to either suppressed or stimulated antitumor responses. This review will discuss the current knowledge regarding the pro- and antitumorigenic roles of neutrophils, leading to the concept of a confused state of neutrophil-driven pro-/antitumor responses.
PRMT3 drives PD-L1-mediated immune escape through activating PDHK1-regulated glycolysis in hepatocellular carcinoma
Aberrant expression of programmed death ligand-1 (PD-L1) facilitates tumor immune evasion. Protein arginine methyltransferase 3 (PRMT3), a member of type I PRMT family, mediates asymmetric dimethylarginine (ADMA) modification of various substrate proteins. This study investigates the role of PRMT3 in PD-L1-associated tumor immunosuppression in hepatocellular carcinoma (HCC). Hepatocyte-specific knockout of Prmt3 significantly suppressed HCC progression in DEN-CCL4-treated mice. Knockout of Prmt3 in HCC cells markedly increased CD8+ T cell infiltration, and reduced lactate production in tumors. PRMT3 interacted with pyruvate dehydrogenase kinase 1 (PDHK1), asymmetric dimethylation of PDHK1 at arginine 363 and 368 residues and increased its kinase activity. The R363/368 K mutant or inhibition of PDHK1 by JX06 blocked the effect of PRMT3 on lactate production. JX06 treatment also attenuated the tumor-promoting role of PRMT3 in HCC in vitro and in vivo. Furthermore, RNA-seq analysis revealed that knockout of PRMT3 downregulates the tumor-associated immune checkpoint, PD-L1, in tumor tissues. Chromatin immunoprecipitation (ChIP) assay demonstrated that PRMT3 promotes lactate-induced PD-L1 expression by enhancing the direct binding of histone H3 lysine 18 lactylation (H3K18la) to the PD-L1 promoter. Tissue microarray analysis showed a positive correlation between PRMT3 and PD-L1 expression in HCC patients. Anti-PD-L1 treatment reversed PRMT3-induced tumor growth and restored CD8+ T cell infiltration. Our research links PRMT3-mediated metabolic reprogramming and immune evasion, revealing that the PRMT3-PDHK1-lactate-PD-L1 axis may be a potential target for improving the efficacy of immunotherapy in HCC.
Enhancer reprogramming: critical roles in cancer and promising therapeutic strategies
Transcriptional dysregulation is a hallmark of cancer initiation and progression, driven by genetic and epigenetic alterations. Enhancer reprogramming has emerged as a pivotal driver of carcinogenesis, with cancer cells often relying on aberrant transcriptional programs. The advent of high-throughput sequencing technologies has provided critical insights into enhancer reprogramming events and their role in malignancy. While targeting enhancers presents a promising therapeutic strategy, significant challenges remain. These include the off-target effects of enhancer-targeting technologies, the complexity and redundancy of enhancer networks, and the dynamic nature of enhancer reprogramming, which may contribute to therapeutic resistance. This review comprehensively encapsulates the structural attributes of enhancers, delineates the mechanisms underlying their dysregulation in malignant transformation, and evaluates the therapeutic opportunities and limitations associated with targeting enhancers in cancer.
Sodium oligomannate disrupts the adherence of Ribhigh bacteria to gut epithelia to block SAA-triggered Th1 inflammation in 5XFAD transgenic mice
Sodium oligomannate (GV-971), an oligosaccharide drug approved in China for treating mild-to-moderate Alzheimer’s disease (AD), was previously found to recondition the gut microbiota and limit altered peripheral Th1 immunity in AD transgenic mice. As a follow-up study, we here made advances by pinpointing a Lactobacillus murinus (L.m.) strain that highly expressed a gene encoding a putative adhesin containing Rib repeats (Ribhigh–L.m.) particularly enriched in 5XFAD transgenic mice. Mechanistically, Ribhigh–L.m. adherence to the gut epithelia upregulated fecal metabolites, among which lactate ranked as the top candidate. Excess lactate stimulated the epithelial production of serum amyloid A (SAA) in the gut via the GPR81-NFκB axis, contributing to peripheral Th1 activation. Moreover, GV-971 disrupted the adherence of Ribhigh–L.m. to gut epithelia via direct binding to Rib, which corrected the excess lactate, reduced SAA, and alleviated Th1-skewed inflammation. Together, we gained further insights into the molecular link between gut bacteria and AD progression and the mechanism of GV-971 in treating AD.
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