Citation: Bouyahya, A.; El Allam, A.; Aboulaghras, S.; Bakrim, S.; El Menyiy, N.; Alshahrani, M.M.; Al Awadh, A.A.; Benali, T.; Lee, L.-H.; El Omari, N.; et al. Targeting mTOR as a Cancer Therapy: Recent Advances in Natural Bioactive Compounds and Immunotherapy. Cancers 2022, 14, 5520. https://doi.org/10.3390/ cancers14225520 Academic Editor: Alberto Maria Martelli Received: 4 October 2022 Accepted: 2 November 2022 Published: 10 November 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/). cancers Review Targeting mTOR as a Cancer Therapy: Recent Advances in Natural Bioactive Compounds and Immunotherapy Abdelhakim Bouyahya 1, * , Aicha El Allam 2 , Sara Aboulaghras 3 , Saad Bakrim 4 , Naoual El Menyiy 5 , Mohammed Merae Alshahrani 6 , Ahmed Abdullah Al Awadh 6 , Taoufiq Benali 7 , Learn-Han Lee 8 , Nasreddine El Omari 9 , Khang Wen Goh 10 , Long Chiau Ming 11, * and Mohammad S. Mubarak 12 1 Laboratory of Human Pathologies Biology, Department of Biology, Faculty of Sciences, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat 10106, Morocco 2 Department of Immunology, Yale University School of Medicine, 333 Cedars Street, TAC S610, New Haven, CT 06519, USA 3 Physiology and Physiopathology Team, Faculty of Sciences, Genomic of Human Pathologies Research, Mohammed V University in Rabat, Rabat 10106, Morocco 4 Geo-Bio-Environment Engineering and Innovation Laboratory, Molecular Engineering, Biotechnologies and Innovation Team, Polydisciplinary Faculty of Taroudant, Ibn Zohr University, Agadir 80000, Morocco 5 Laboratory of Pharmacology, National Agency of Medicinal and Aromatic Plants, Taounate 34025, Morocco 6 Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Najran University, 1988, Najran 61441, Saudi Arabia 7 Environment and Health Team, Polydisciplinary Faculty of Safi, Cadi Ayyad University, Sidi Bouzid B.P. 4162, Morocco 8 Novel Bacteria and Drug Discovery Research Group (NBDD), Microbiome and Bioresource Research Strength (MBRS), Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Malaysia 9 Laboratory of Histology, Embryology, and Cytogenetic, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat 10100, Morocco 10 Faculty of Data Science and Information Technology, INTI International University, Nilai 71800, Malaysia 11 Pengiran Anak Puteri Rashidah Sa’adatul Bolkiah Institute of Health Sciences, Universiti Brunei Darussalam, Gadong BE1410, Brunei 12 Department of Chemistry, The University of Jordan, Amman 11942, Jordan * Correspondence: bouyahya@um5r.ac.ma (A.B.); longchiauming@gmail.com (L.C.M.) Abstract: The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine- protein kinase, which regulates many biological processes related to metabolism, cancer, immune function, and aging. It is an essential protein kinase that belongs to the phosphoinositide-3-kinase (PI3K) family and has two known signaling complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Even though mTOR signaling plays a critical role in promoting mitochondria- related protein synthesis, suppressing the catabolic process of autophagy, contributing to lipid metabolism, engaging in ribosome formation, and acting as a critical regulator of mRNA translation, it remains one of the significant signaling systems involved in the tumor process, particularly in apoptosis, cell cycle, and cancer cell proliferation. Therefore, the mTOR signaling system could be suggested as a cancer biomarker, and its targeting is important in anti-tumor therapy research. Indeed, its dysregulation is involved in different types of cancers such as colon, neck, cervical, head, lung, breast, reproductive, and bone cancers, as well as nasopharyngeal carcinoma. Moreover, recent investigations showed that targeting mTOR could be considered as cancer therapy. Accordingly, this review presents an overview of recent developments associated with the mTOR signaling pathway and its molecular involvement in various human cancer types. It also summarizes the research progress of different mTOR inhibitors, including natural and synthetised compounds and their main mechanisms, as well as the rational combinations with immunotherapies. Keywords: mTOR; immunotherapy; cancer; natural drugs; mTOR inhibitors Cancers 2022, 14, 5520. https://doi.org/10.3390/cancers14225520 https://www.mdpi.com/journal/cancers