  Citation: Setlai, B.P.; Hull, R.; Bida, M.; Durandt, C.; Mulaudzi, T.V.; Chatziioannou, A.; Dlamini, Z. Immunosuppressive Signaling Pathways as Targeted Cancer Therapies. Biomedicines 2022, 10, 682. https://doi.org/10.3390/ biomedicines10030682 Academic Editors: Demin Cai and Chengfei Liu Received: 10 February 2022 Accepted: 11 March 2022 Published: 16 March 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 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) license (https:// creativecommons.org/licenses/by/ 4.0/). biomedicines Review Immunosuppressive Signaling Pathways as Targeted Cancer Therapies Botle Precious Setlai 1, * , Rodney Hull 2 , Meshack Bida 3 , Chrisna Durandt 4 , Thanyani Victor Mulaudzi 1 , Aristotelis Chatziioannou 5 and Zodwa Dlamini 2, * 1 Department of Surgery, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Arcadia 0007, South Africa; thanyani.mulaudzi@up.ac.za 2 SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa; rodneyhull@gmail.com 3 Department of Anatomical Pathology, National Health Laboratory Service (NHLS), University of Pretoria, Hatfield 0028, South Africa; meshack.bida@nhls.ac.za 4 Institute for Cellular and Molecular Medicine, Department of Immunology, SAMRC Extramural Unit for Stem Cell Research and Therapy, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; chrisna.durandt@up.ac.za 5 Center of Systems Biology, Biomedical Research Foundation Academy of Athens, 4 Soranou Ephessiou Str., 115 27 Athens, Greece; achatzi@bioacademy.gr * Correspondence: precious.setlai@up.ac.za (B.P.S.); Zodwa.Dlamini@up.ac.za (Z.D.) Abstract: Immune response has been shown to play an important role in defining patient prognosis and response to cancer treatment. Tumor-induced immunosuppression encouraged the recent development of new chemotherapeutic agents that assists in the augmentation of immune responses. Molecular mechanisms that tumors use to evade immunosurveillance are attributed to their ability to alter antigen processing/presentation pathways and the tumor microenvironment. Cancer cells take advantage of normal molecular and immunoregulatory machinery to survive and thrive. Cancer cells constantly adjust their genetic makeup using several mechanisms such as nucleotide excision repair as well as microsatellite and chromosomal instability, thus giving rise to new variants with reduced immunogenicity and the ability to continue to grow without restrictions. This review will focus on the central molecular signaling pathways involved in immunosuppressive cells and briefly discuss how cancer cells evade immunosurveillance by manipulating antigen processing cells and related proteins. Secondly, the review will discuss how these pathways can be utilized for the implementation of precision medicine and deciphering drug resistance. Keywords: immunosuppression; immune evasion; PI3K pathway inhibitors; precision medicine; cancer cells 1. Introduction Studies pertaining to the role of genomic instability in immuno and chemotherapeutic response are still a topic of interest, particularly in colorectal cancers [1–3]. This is due to the heterogenicity of these mutations within the different tumor microenvironments. Molecularly targeted therapies have been developed to target or block signaling pathways specific to a certain cancer type. This allows cancers to be sensitized to chemotherapy [4] or immunotherapy [5]. Despite the efforts to halt cancer progression at the DNA level, cancer can still persist and develop the ability to manipulate and evade the immune system. Cancer cells utilize various mechanisms to proliferate and survive. These cells take advantage of the normal functioning immunoregulatory processes and their related biochemical pathways to create a suitable environment for them to survive and thrive. These include the activities of immunosuppressive cells and the action of cytokines such as interleukin (IL)-10 and transforming growth factor-β (TGF-β)[6]. Immune checkpoints (ICs) are surface proteins Biomedicines 2022, 10, 682. https://doi.org/10.3390/biomedicines10030682 https://www.mdpi.com/journal/biomedicines