Chemo-Radio-Immunotherapy Strategies to Prevent Immune Resistance in Non-Small Cell Lung Cancer

Immunotherapy (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 key words 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.