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Tetrahydrobiopterin is a cofactor necessary for the activity of several enzymes, the most studied of which is nitric oxide synthase. The role of this cofactor-enzyme relationship in vascular biology is well established. Recently, tetrahydrobiopterin metabolism has received increasing attention in the field of cancer immunology and immunotherapy due to its involvement in the cytotoxic T cell response. Past research has demonstrated that when the availability of BH4 is low, as it is in chronic inflammatory conditions and tumors, electron transfer in the active site of nitric oxide synthase becomes uncoupled from the oxidation of arginine. This results in the production of radical species that are capable of a direct attack on tetrahydrobiopterin, further depleting its local availability. This feedforward loop may act like a molecular switch, reinforcing low tetrahydrobiopterin levels leading to altered NO signaling, restrained immune effector activity, and perpetual vascular inflammation within the tumor microenvironment. In this review, we discuss the evidence for this underappreciated mechanism in different aspects of tumor progression and therapeutic responses. Furthermore, we discuss the preclinical evidence supporting a clinical role for tetrahydrobiopterin supplementation to enhance immunotherapy and radiotherapy for solid tumors and the potential safety concerns., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Clark, Lai, Agarwal, Liu and Wang.)

Opioid overdose is a leading cause of death in the United States, and engaging with patients following overdose to provide harm reduction and recovery resources can prove difficult. Quick response models use mobile, multidisciplinary teams to establish a time-sensitive connection between individuals who overdosed and harm reduction and recovery resources that improve outcomes. These quick response models are consistent with the broader field of mobile-integrated health programs that are growing in number and acceptability, though the literature base is sparse and programs vary. We describe the 5-year reach, effectiveness, adoption, implementation and maintenance (RE-AIM) framework of the Rapid Response Emergency Addiction and Crisis Team (RREACT), a fire/emergency medical services-led, multidisciplinary (firefighter/paramedic, law enforcement officer, social worker) mobile outreach team. RREACT provides harm reduction, linkage/transportation to care and wrap-around services to individuals following a nonfatal opioid overdose that resulted in an emergency response in Columbus, Franklin County, Ohio, United States. Between 2018 and 2022, RREACT made 22,157 outreach attempts to 11,739 unique patients. RREACT recorded 3,194 direct patient contacts during this time, resulting in 1,200 linkages to care: 799 direct transports to opioid use disorder treatment and 401 warm handoffs to community treatment agencies. Furthermore, RREACT's staffing increased from 4 full-time equivalent staff in 2018 to 15.5 in 2022 and was supported by the surrounding community through 287 community outreach events and the development of an alumni program. These preliminary results further support the deployment of multidisciplinary mobile outreach teams to increase access to harm reduction and recovery resources following opioid overdose., Competing Interests: CONFLICT OF INTEREST DISCLOSURE Mighty Crow Media, LLC, employs an author of this article and serves as the grant evaluator for RREACT’s Bureau of Justice Assistance COSSAP grant. Grant funding does not support time or other costs associated with this publication. Alexander Ulintz was supported by AHRQ T32 grant (T32 HS029590).