The human gut is inhabited by hundreds of billions of commensal microbiota that collectively produce thousands of small molecules and metabolites with local and systemic effects on the physiology of the host. Much evidence from preclinical to clinical studies has gradually confirmed that the gut microbiota can regulate anti-tumor immunity and affect the efficacy of cancer immune checkpoint inhibitors (ICIs) therapy. In particular, one of the main modes of gut microbiota regulating anti-tumor immunity is through metabolites, which are small molecules that can be transported in the body and act on local and systemic anti-tumor immune responses to promote ICIs immunotherapy efficacy. We discuss the functions of microbial metabolites in humans, focusing on the effects and mechanisms of microbial metabolites on immunotherapy, and analyze their potential applications as immune adjuvants and therapeutic targets to regulate immunity and enhance ICIs. In summary, this review provides the basis for the rational design of microbiota and microbial metabolite-based strategies of enhancing ICIs.

Ulcerative colitis (UC) is a recurrent inflammatory disease related to gut microbiota disorder. Metabolites and their sensors play an important role in the communication between gut microbes and their host. Our previous study revealed that G protein‐coupled receptor 35 (GPR35) is a key guardian of kynurenic acid (KA) and a core element of the defense responses against gut damage. However, the mechanism remains unknown. In this study, a DSS‐induced rat colitis model was established and 16S rRNA sequencing was applied to explore the influence of GPR35‐mediated KA sensing on gut microbiota homeostasis. Our results demonstrated that GPR35‐mediated KA sensing is a necessary component in maintaining gut barrier integrity against DSS‐induced damage. Furthermore, we provide compelling evidence suggesting that GPR35‐mediated KA sensing plays a crucial role in maintaining gut microbiota homeostasis, which contributes to alleviation of DSS‐induced colitis. In addition, five classes (Actinobacteria, Beta‐/Gamma‐proteobacteria, Erysipelotrichi, and Coriobacteriia) and six genera (Corynebacterium, Allobaculum, Parabacteroides, Sutterella, Shigella, and Xenorhabdus) were identified as the marked bacterial taxa that characterized the progression and outcome of colitis and are regulated by GPR35‐mediated KA sensing. Our findings highlight that GPR35‐mediated KA sensing is an essential defense mechanism against disorder of gut microbiota in UC. The results provide insights into the key role of specific metabolites and their monitor in maintaining gut homeostasis.

In this paper, two new iridium (III) complexes, [Ir(ppy)₂(ipbp)](PF₆) (Ir1) (ppy = 2-phenylpyridine, ipbp = 3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2yl)-4H-chromen-4-one) and [Ir(bzq)₂(ipbp)](PF₆) (Ir2) (bzq = benzo[h]quinolone), were synthesized and characterized. The cytotoxicity of the complexes against human colon cancer HCT116 and normal LO2 cells was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The complexes Ir1 and Ir2 show high cytotoxic efficacy toward HCT116 cells with a low IC₅₀ value of 1.75 ± 0.10 and 6.12 ± 0.2 µM. Interestingly, Ir1 only kills cancer cells, not normal LO2 cells (IC₅₀ > 200 µM). The inhibition of cell proliferation and migration were investigated by multiple tumor spheroid (3D) and wound healing experiments. The cellular uptake was explored under a fluorescence microscope. The intracellular reactive oxygen species (ROS), change of mitochondrial membrane potential, glutathione (GSH) and adenine nucleoside triphosphate (ATP) were studied. Apoptosis and cell cycle arrest were performed by flow cytometry. The results show that the complexes induce early apoptosis and inhibit the cell proliferation at the G0/G1 phase. Additionally, the apoptotic mechanism was researched by Western blot analysis. The results obtained demonstrate that the complexes cause apoptosis in HCT116 cells through ROS-mediated mitochondrial dysfunction and the inhibition of PI3K/AKT signaling pathways.

The impaired repair of intestinal mucosal damage is an important pathological feature of ulcerative colitis (UC). The critical role of intestinal epithelial cells (IECs) proliferation and migration in the repair of damaged mucosal epithelium has been well established. However, the molecular circuitry that decodes IECs sense intestinal mucosal damage signals to initiate and drive repair program remains elusive. Here, we identify a tryptophan (Trp) metabolic gatekeeping mechanism wherein G protein-coupled receptor 35 (GPR35) senses intestinal mucosal damage through monitoring Trp-kynurenine (KYN)-kynurenic acid (KA) axis metabolism with a unique “sandwich” structural binding mode. We delineate a GPR35-Kruppel-like factor 5 (KLF5) regulatory circuit in which KLF5 serves as the central effector, translating GPR35-mediated KA sensing into repair programming through PI3K-AKT-mTOR signaling cascade. This circuitry precisely orchestrates IECs proliferation and migration by regulating KLF5-dependent gene expression networks that essential for restoring damaged mucosa. Once this metabolic gatekeeping system is disrupted, either through impaired GPR35-mediated KA sensing or defective signal transduction, compromises damage signal decoding, leading to inadequate repair responses. Such dysregulation results in delayed intestinal mucosal repair and exacerbation of tissue damage. Our findings highlight GPR35 as a surveillant of abnormal Trp-KYN-KA axis metabolism, enabling IECs to detect intestinal mucosal damage and orchestrate repair through KLF5 response. This provides important implications for UC prevention and treatment by targeting GPR35-KLF5 circuit.

Physical activity is frequently proposed as an intervention to reduce fatigue and sleep disturbance in cancer survivors; however, the long-term effects of physical activity are often not reported, and older adults are typically excluded from these intervention studies. This article aimed to examine if postdiagnosis physical activity is associated with lower long-term fatigue and sleep disturbance in older adult breast cancer survivors. Data were analyzed of a prospective cohort of 440 breast cancer survivors aged 65 years or older from the Women’s Health Initiative study. Multiple linear and logistic regression models were used to examine associations of physical activity with fatigue and sleep disturbance. Higher postdiagnosis physical activity was associated with lower long-term fatigue but was not associated with lower sleep disturbance after adjusting for demographics, cancer characteristics, and baseline measures.