Overcoming immunosuppression in the tumor microenvironment (TME) is crucial for developing novel cancer immunotherapies. Here, we report that IL-16 administration enhances the polarization of T helper 1 (Th1) cells by inhibiting glutamine catabolism through the downregulation of glutaminase in CD4⁺ T cells and increases the production of Th1 effector cytokine IFN-γ, thus improving anti-tumor immune responses. Moreover, we find that establishing an IL-16-dependent, Th1-dominant TME relies on mast cell-produced histamine and results in the increased expression of the CXCR3 ligands in tumor-associated macrophages (TAM), thereby improving the therapeutic effectiveness of immune checkpoint blockade (ICB). Cancer patients exhibit impaired production of IL-16, which correlates with poorer prognosis. Additionally, low IL-16 production is associated with unresponsiveness to immunotherapy in cancer patients. Collectively, our findings provided new insights into the biological function of IL-16, emphasizing its potential clinical significance as a therapeutic approach to augment anti-tumor immunity and sensitize ICB-based cancer immunotherapy.

Myocardial ischemia reperfusion (I/R) injury is a complex process with intense inflammatory response and cardiomyocyte apoptosis. As a decoy receptor of IL-1β, Interleukin-1 receptor type 2 (IL-1R2) inhibits IL-1β signaling. However, its role in I/R injury remains unknown. Here we found that the serum levels of IL-1R2 were significantly increased in patients with acute myocardial infarction (AMI) following interventional therapy. Similarly, after myocardial I/R surgery, IL-1R2 expression was significantly increased in heart of wild-type mice. In addition, IL-1R2-deficient mice heart showed enlarged infarct size, increased cardiomyocyte apoptosis together with reduced cardiac systolic function. Following exposure to hypoxia and reoxygenation (H/R), neonatal rat ventricular myocytes (NRVM) significantly increased IL-1R2 expression relying on NF-κB activation. Consistently, IL-1R2-deficient mice increased immune cells infiltrating into heart after surgery, which was relevant with cardiac damage. Additionally, IL-1R2 overexpression in cardiomyocyte protected cardiomyocyte against apoptosis through reducing the IL-17RA expression both in vivo and in vitro. Our results indicate that IL-1R2 protects cardiomyocytes from apoptosis, which provides a therapeutic approach to turn down myocardial I/R injury.

An active lifestyle protects against cardiovascular diseases, yet its mechanisms in modulating the cardiac immune environment and preserving cardiac function remain unclear. Here, we identify a subpopulation of monocyte-derived cardiac macrophages, termed iNOS ⁺ Arg1 ⁺ macrophages, which simultaneously express pro-inflammatory and pro-reparative genes in exercised male mice. Inhibiting either pro-inflammatory iNOS or pro-reparative Arg1 in these macrophages counters the exercise-induced cardiac function preservation. Mechanistically, exercise enhances glycolysis in monocytes, increasing lactate production and driving histone lactylation at H3K18, mediated by p300 as the relevant lactyltransferase and counterbalanced by HDAC2 as deacetylase. H3K18la accelerates the transition of cardiac macrophages to a pro-reparative state, restoring immune homeostasis and preserving cardiac function. Notably, human monocytes from physically active individuals exhibit elevated levels of Pan-Kla and H3K18la compared to those from sedentary individuals. Importantly, adoptive transfer of highly histone-lactylated monocytes restores cardiac function in sepsis-induced cardiomyopathy, which might translate into a promising therapeutic strategy for cardiomyopathy.