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The study aims to clarify mechanisms driving resistance across tumor cells, the tumor microenvironment, and the host to identify strategies to counter it. Literature evidence is used to evaluate the synergy of immunotherapy with chemotherapy and/or radiotherapy and its dual effects on the microenvironment. 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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.  \n1 Faculty of Medicine, University of Medicine and Pharmacy “Iuliu Hatieganu”, 8 Victor Babes Street, 400012 Cluj-Napoca, Romania; [andreapatraulea@gmail.com](andreapatraulea@gmail.com) (R.-A.R.-P.)  \n2 Radiotherapy Laboratory, Oncology Institute “Prof. Dr. Ion Chiricuta”, 34-36 Republicii Street,  \n400015 Cluj-Napoca, Romania  \n* [Correspondence: petronelarusu@yahoo.com](Correspondence: petronelarusu@yahoo.com); Tel.: +40-724370223  \nSimple Summary  \nImmunotherapy and especially immune checkpoint blockade changed therapeutic approaches in non-small cell lung cancer. Nevertheless, primary or secondary resistance anda percentage of long responders and survivors have been observed. The aim of this study is to gain a deeper understanding of the complex mechanisms of primary and secondary resistance to immunotherapy in order to find strategies to overcome it. The most widely used approach is the combination of immunotherapy with chemotherapy and/or radiotherapy, relying on the synergistic effect on the enhancement of immunogenic cell death. However, a dual role has been observed, considering in particular the complex effect on the tumor microenvironment. Preclinical and clinical studies investigate the best sequencing of chemoradiation with immunotherapy and the optimal radiotherapy volumes, sites, and dose/fractionation regimens; dynamic biomarkers are necessary in order to guide decisions. Moving forward, multiple agents addressing coinhibitory or costimulatory receptors on immune or tumor cells are under evaluation.  \nAbstract  \nImmunotherapy (IT) and especially immune checkpoint blockade (ICB) changed the therapeutic approach in non-small cell lung cancer (NSCLC). Nevertheless, primary or secondary resistance and a percentage of long responders and survivors have been observed. The aim of this study is to gain a deeper understanding of the complex mechanisms of primary and secondary resistance to IT, involving tumor cells, the tumor microenvironment (TME), and the host, in order to find strategies to overcome it. With this aim in mind, a search for keywords has been performed to identify relevant evidence in the literature. The most widely used approach is the combination of IT with chemotherapy (CT) and/or radiotherapy (RT), relying on the synergistic effect on the enhancement of immunogenic cell death. Since a dual role has been observed, a lot of questions are yet to be answered regarding the complex effect of these therapies, especially on the TME. Preclinical and clinical studies investigate the best sequencing and timing of chemoradiation with IT, and the optimal RT volumes, sites, and dose/fractionation regimens to favor immune stimulation over suppression on the TME. Moving forward, multiple agents addressing coinhibitory or costimulatory receptors on immune or tumor cells are under evaluation. The huge potential of combination therapies becoming apparent. Questions regarding targets, selection of patients, and time and sequence of administration are yet to be answered, considering the complex mechanisms of resistance. Dynamic biomarkers to guide personalized treatment decisions are needed.  \nKeywords: chemo-radio-immunotherapy; immune resistance; NSCLC  \n1. Introduction  \nIn the last decade, IT and especially immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and changed the therapeutic strategies in lung cancer, the most frequently diagnosed cancer, with 2.5 mill","cbCaitEgZBjLKd4Z","https://ap.wps.com/l/cbCaitEgZBjLKd4Z","pdf",341020,18,"English","# Simple Summary\n# Abstract\n# Keywords\n# 1. Introduction\n## 1.1. Cancer Immune Surveillance and Immunoediting","[{\"question\":\"What problem does the study address in non-small cell lung cancer immunotherapy?\",\"answer\":\"It focuses on primary and secondary resistance and the limited proportion of long responders and survivors despite immune checkpoint blockade. The goal is to understand the mechanisms behind resistance to enable overcoming it.\"},{\"question\":\"Why are chemotherapy and radiotherapy combined with immunotherapy in this context?\",\"answer\":\"The document highlights that the combination is widely used because it can enhance immunogenic cell death through synergistic effects. However, it can also act bidirectionally, producing complex outcomes in the tumor microenvironment.\"},{\"question\":\"What research directions does the document emphasize for improving treatment decisions?\",\"answer\":\"It emphasizes identifying optimal sequencing and timing of chemoradiation with immunotherapy, determining suitable radiotherapy volumes and dose/fractionation regimens, and developing dynamic biomarkers to guide personalized decisions.\"}]","Chemo-Radio-Immunotherapy Strategies to Prevent Immune Resistance in Non-Small Cell Lung Cancer | PDF",1790774993,45]