CO-induced TTP improves efficacy through resetting tumor-associated macrophages toward M1 phenotype in combined CTLA-4 and PD-1 blockade immunotherapy

Abstract Combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 has improved the prognosis for many malignancies, but also occurred a high rate of immune-related adverse events (irAEs). The manifestation these toxicities is an important limiting factor successful implementation CICB, restraining its anti-tumor efficacy. Carbon monoxide (CO), pivotal endogenous signaling molecule, able to maintain cell tissue homeostasis could be used as therapeutic regimen. In our previous reports, CO useful therapeutics regulation various inflammatory diseases through increase tristetraprolin (TTP) that binds AU-rich elements in target mRNA. this study, we observed CO-induced TTP activation ameliorated colitis hepatitis, efficacy CICB treatment. We found hepatitis deficient mice were further exacerbated by Moreover, increases TAM M1 polarization together with diminishes irAEs enhancement several organ. Thus, suggest might efficiently decouples toxicity enhancement.