Kgatle, MankgopoBoshomane, Tebatso M.G.Lawal, Ismaheel OpeyemiMokoala, Kgomotso M.G.Mokgoro, Neo P.Lourens, NicoKairemo, KalevoZeevaart, Jan RijnVorster, MarizaSathekge, Mike Machaba2022-04-112022-04-112021-04-15Kgatle, M.M.; Boshomane, T.M.G.; Lawal, I.O.; Mokoala, K.M.G.; Mokgoro, N.P.; Lourens, N.; Kairemo, K.; Zeevaart, J.R.; Vorster, M.; Sathekge, M.M. Immune Checkpoints, Inhibitors and Radionuclides in Prostate Cancer: Promising Combinatorial Therapy Approach. International Journal of Molecular Sciences 2021, 22, 4109. https://DOI.org/10.3390/ijms22084109.1661-6596 (print)1422-0067 (online)10.3390/ijms22084109https://repository.up.ac.za/handle/2263/84864Emerging research demonstrates that co-inhibitory immune checkpoints (ICs) remain the most promising immunotherapy targets in various malignancies. Nonetheless, ICIs have offered insignificant clinical benefits in the treatment of advanced prostate cancer (PCa) especially when they are used as monotherapies. Current existing PCa treatment initially offers an improved clinical outcome and overall survival (OS), however, after a while the treatment becomes resistant leading to aggressive and uncontrolled disease associated with increased mortality and morbidity. Concurrent combination of the ICIs with radionuclides therapy that has rapidly emerged as safe and effective targeted approach for treating PCa patients may shift the paradigm of PCa treatment. Here, we provide an overview of the contextual contribution of old and new emerging inhibitory ICs in PCa, preclinical and clinical studies supporting the use of these ICs in treating PCa patients. Furthermore, we will also describe the potential of using a combinatory approach of ICIs and radionuclides therapy in treating PCa patients to enhance efficacy, durable cancer control and OS. The inhibitory ICs considered in this review are cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1), V-domain immunoglobulin suppressor of T cell activation (VISTA), indoleamine 2,3-dioxygenase (IDO), T cell Immunoglobulin Domain and Mucin Domain 3 (TIM-3), lymphocyteactivation gene 3 (LAG-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), B7 homolog 3 (B7-H3) and B7-H4.en© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) licenseImmune checkpointsImmune checkpoints inhibitorsImmunotherapyMetastatic hormone resistance prostate cancerMetastatic hormone sensitive prostate cancerProstate cancerPeptide receptor ligand therapyRadionuclidesProstate specific membrane antigenArticle