Abstract
Abstract Tumor-associated macrophages (TAMs) often impede immunotherapy success by promoting an immune-suppressive environment in the tumor. Depleting TAMs directly has shown limited success in clinics due to challenges in precise targeting and avoiding toxic side effects. An alternative approach involves targeting circulating monocytes (CMs), the precursors of TAMs. In inflammatory conditions like cancer, CMs replace exhausted tissue-resident macrophages. Our study found that anti-PD-1 responders had elevated CM numbers before treatment, correlating with increased anti-tumorigenic macrophages in tumors. Analyzing CMs revealed higher sphingosine 1-phosphate (S1P) levels in responder patients, crucial for immune cell bioenergetics. Preliminary experiments using S1P/SK2 treatment improved CM function, supporting T cell proliferation and enhancing checkpoint inhibition therapy response. Exploring the S1P/SK2 pathway's impact on CM-derived macrophages and in vivo behavior is ongoing. Targeting the S1P/SK2 pathway to reprogram CM for anti-tumorigenic macrophage generation epigenetically shows promise in enhancing cancer immunotherapy efficacy, with potential implications for treating diverse diseases beyond cancer.
Published Version
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