ABSTRACT Lactate, once regarded merely as the terminal product of glycolysis, is now recognised as a pivotal immunometabolic regulator that actively shapes inflammatory responses. However, accumulating evidence reveals an apparent paradox that lactate can either amplify immune activation or promote inflammation resolution depending on the biological context. The mechanisms underlying this functional duality remain incompletely understood, limiting the development of effective lactate‐targeted therapies. In this review, we propose that lactate functions as a context‐dependent immunometabolic rheostat whose Yin‐Yang properties are determined by the integration of four key factors: lactate concentration, cellular identity, disease stage and inflammatory microenvironment. We summarise how lactate regulates immune responses through coordinated control of metabolic reprogramming, intercellular lactate shuttling, receptor‐mediated signalling, intracellular sensing, and protein lactylation, thereby orchestrating the activation and resolution of inflammation. We further discuss the cell‐specific actions of lactate across endothelial cells, macrophages, fibroblast‐like synoviocytes, neutrophils, and lymphocytes, highlighting how these mechanisms collectively remodel the inflammatory microenvironment. Beyond mechanistic insights, we examine evidence from representative inflammatory disease models, including rheumatoid arthritis, sepsis, and atherosclerosis, and evaluate emerging therapeutic strategies targeting lactate production, transport, sensing and metabolism. Rather than advocating indiscriminate lactate inhibition, current evidence supports context‐specific modulation of lactate signalling according to disease stage and immune landscape.
ABSTRACT Natural killer (NK) cells are innate lymphocytes, which are critical for the antitumor immunity response against tumour cells. However, the function of NK cells is frequently compromised in hepatocellular carcinoma (HCC). In this study, we found that CCAT1 expression level was reduced in peripheral blood (PB)‐NK cells derived from HCC patients, compared to PB‐NK cells derived from healthy controls. Reduced CCAT1 expression in NK cells was associated with poor disease‐free survival and overall survival of HCC patients. Gain‐ and loss‐of‐function assays revealed that CCAT1 restored NK cell cytotoxicity in vitro and also restored NK cell antitumor activity in vivo. Mechanistic investigations found that CCAT1 upregulated c‐Myc in NK cells. c‐Myc directly bound TBX21 promoter and activated TBX21 transcription, leading to the increase of T‐bet which is encoded by TBX21 . Through upregulating c‐Myc, CCAT1 increased T‐bet expression. Functional rescue assays showed that the function of CCAT1 in NK cells was dependent on c‐Myc and T‐bet. The expression of CCAT1 , MYC and TBX21 was positively correlated with each other in NK cells derived from HCC patients. Collectively, this study provided mechanistic insight into NK cell dysfunctionality in HCC and suggested that restoring CCAT1 in NK cells represented a potential NK‐cell‐targeting immunotherapeutic strategy for HCC.
ABSTRACT Lung cancer‐mediated myeloid‐derived suppressor cell (MDSC) inhibits antitumour immunity for tumour progression and is a promising target. Here, we present the ADAM9‐targeting therapeutic strategy to unleash anticancer immunity. We identified a novel role for ADAM9 in promoting lung cancer immunosuppression through the upregulation of cytokines that drive the recruitment and expansion of MDSCs, with CXCL12 serving as one of the major mediators. This ADAM9–CXCL12–MDSC axis significantly impairs the function of cytotoxic CD8+ T cells. Disrupting the ADAM9–CXCL12 axis suppresses oncogenic signalling pathways, including EGFR and IL‐6 signalling. Therapeutically, the developed ADAM9 inhibitors significantly reduced primary tumour growth and metastasis in syngeneic mouse models of lung tumours, concurrent with remodelling of the immune microenvironment. This study demonstrates that ADAM9 promotes cancer‐mediated MDSC function by enhancing CXCL12 production. Targeting ADAM9 represents a novel and effective strategy to reverse the immunosuppressive tumour microenvironment and suppress lung cancer progression.
