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 approaches in non-small cell lung cancer (NSCLC). Still, primary or second-ary resistance and a percentage of long responders and survivors have been observed. The objective is to have a deeper understanding of the complex mechanisms of primary and secondary resistance to IT involving tumor cells, TME and host, to find strategies to over-come it. In this aim a search of the key words has been performed to identify the relevant evidence in the literature. The most available approach thus far is the combination of IT with chemotherapy (CT) and/or radiotherapy (RT), relying on the synergistic effect in enhancement of immunogenic cell death. Even so, a lot of questions are to be answered, as a dual role has been observed, considering the complex effect, especially on the TME. Preclinical and clinical studies investigate the best sequencing and timing of chemoradiation with IT, the optimal RT volumes, sites, dose/fractionation regimens, to favor immunostimulation over suppression on the TME. Moving forward, multiple agents addressing coinhibitory or costimulatory receptors, on immune or tumor cells, are under evalua-tion. In perspective, a huge potential of combination therapies is arising, but to which tar-get, to what patient, at what time and sequence to be administered, considering the complex mechanisms of resistance, needs dynamic biomarkers to guide the decisions, to-wards more personalized treatments.