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Despite major progress, only a limited number of immunotherapeutic options have been approved for difficult solid tumors including triple negative breast cancer, glioblastoma multiforme, and advanced prostate cancer. These cancers are often challenging to treat due to their anatomical features. The review integrates microbiota- and lifestyle-linked factors—such as diet, stress, social support, exercise, sleep, and oral hygiene—alongside recent therapies to inform future treatment 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Triple Negative Breast Cancer, and Advanced Prostate Cancer  \nCarles Puig-Saenz 1,2, Joshua R. D. Pearson 1,2, Jubini E. Thomas 1,2 and St²phanie E. B. McArdle 1,2, *  \nCitation: Puig-Saenz, C.; Pearson, J.R.D.; Thomas, J.E.; McArdle, S.E.B. A Holistic Approach to Hard-to-Treat Cancers: The Future of Immunotherapy for Glioblastoma, Triple Negative Breast Cancer, and Advanced Prostate Cancer.  \nBiomedicines 2023, 11, 2100 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)biomedicines11082100  \nAcademic Editor: Satoshi Wada  \nReceived: 27 June 2023  \nRevised: 21 July 2023  \nAccepted: 24 July 2023  \nPublished: 25 July 2023  \nCopyright: © 2023 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://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 The John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, College Drive, Clifton, Nottingham NG11 8NS, UK; [carles.puigsaenz2016@my.ntu.ac.uk](carles.puigsaenz2016@my.ntu.ac.uk) (C.P.-S.); [jrdpearson@hotmail.co.uk](jrdpearson@hotmail.co.uk) (J.R.D.P.); [jubini.thomas2020@my.ntu.ac.uk](jubini.thomas2020@my.ntu.ac.uk) (J.E.T.)  \n2 Centre for Systems Health and Integrated Metabolic Research, School of Science and Technology, Nottingham Trent University, College Drive, Clifton, Nottingham NG11 8NS, UK  \n* Correspondence: [stephanie.mcardle@ntu.ac.uk](stephanie.mcardle@ntu.ac.uk); Tel.: +44-(0)1158483136  \nAbstract: Immunotherapy represents an attractive avenue for cancer therapy due to its tumour specificity and relatively low frequency of adverse effects compared to other treatment modalities. Despite many advances being made in the field of cancer immunotherapy, very few immunotherapeutic treatments have been approved for difficult-to-treat solid tumours such as triple negative breast cancer (TNBC), glioblastoma multiforme (GBM), and advanced prostate cancer (PCa) . The anatomical location of some of these cancers may also make them more difficult to treat. Many trials focus solely on immunotherapy and have failed to consider or manipulate, prior to the immunotherapeutic intervention, important factors such as the microbiota, which itself is directly linked to lifestyle factors, diet, stress, social support, exercise, sleep, and oral hygiene. This review summarises the most recent treatments for hard-to-treat cancers whilst factoring in the less conventional interventions which could tilt the balance of treatment in favour of success for these malignancies.  \nKeywords: glioblastoma; triple negative breast cancer; advanced prostate cancer; microbiota; stress; exercise; immunotherapy; vaccine  \n1. Introduction  \nImmunotherapy, such as the use of checkpoint inhibitors, oncolytic virus, bispecific antibodies, and adoptive cell transfer, has revolutionised the treatment of many cancers. Today, many of these approaches have been FDA approved for the treatment of several cancers [1] . Talimogene laherparepvec (T-VEC) is an oncolytic virus, FDA approved in 2015, for the treatment of advanced melanoma (stage IIIB-IV) [2] and Mosunetuzumab-axgb is a bispecific antibody approved for the treatment of adults with relapsed or refractory follicular lymphoma; in addition, three other bispecific antibodies have recently been approved for the treatment of acute lymphoblastic leukaemia (Blincyto), for non-small cell lung cancer (Rybrevant), and for uveal melanoma (Kimmtrak) . In terms of cellular therapy, FDA-approved treatment using chimeric antigen receptor T (CAR-T) has been limited to B cell malignancies expressing CD19 and, while these harbour high potential for solid tumours, they","cbCaigtQg3MqlS51","https://ap.wps.com/l/cbCaigtQg3MqlS51","pdf",921133,24,"English","# Abstract\n# Keywords\n# 1. Introduction\n# 2. Glioblastoma (GBM)","[{\"question\":\"Why is immunotherapy considered attractive for cancer therapy in this review?\",\"answer\":\"Immunotherapy is presented as attractive because it targets tumors with specificity and is associated with relatively fewer adverse effects compared with other treatment modalities.\"},{\"question\":\"Which difficult-to-treat cancers does the review focus on?\",\"answer\":\"The review focuses on triple negative breast cancer, glioblastoma multiforme, and advanced prostate cancer, describing why these tumors are difficult to manage.\"},{\"question\":\"How does the review connect immunotherapy outcomes with lifestyle-related factors?\",\"answer\":\"It argues that trials often focus on immunotherapy alone and do not sufficiently account for or manipulate factors such as the microbiota, which is linked to lifestyle elements including diet, stress, social support, exercise, sleep, and oral hygiene.\"}]","A Holistic Approach to Hard-to-Treat Cancers - The Future of Immunotherapy for Glioblastoma, Triple Negative Breast Cancer, and Advanced Prostate Cancer | PDF",1790260501]