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Future immunotherapies will be based on cycles of interventions designed to boost and modulate anti-cancer immunity ( Figure 4 ). Indeed, as we rediscover and refine the fundamental principles of tumor immunology, it is increasingly clear that curing cancer might not be a realistic goal. Rather, aiming for a continuum of treatment cycles designed and based on mechanistic in vivo studies and in-depth analysis of each patient’s tumor will be necessary for optimizing outcomes. Clinical trials with checkpoint inhibitors teach us that in situ immune infiltration is critical for tumor regression; however, not all immune infiltrates are equal, and as discussed throughout this article, the quality of immune response is a critical factor for therapeutic success. This, in turn, is determined by underlying inflammation, which we assert must become a staging parameter, along with classical pathology-based schemas and the Immunoscore. It will also need to be established to what extent inflammation, which clearly plays a role in epithelial tumors, impacts other tumor types, e.g., melanoma or sarcomas. Additional parameters pertain to the specificity of infiltrating T cells against cancer antigens, as again, the infiltrate with passenger T cells might not be therapeutically useful and should be tested. Eventually all patients will be treated with checkpoint inhibitors, either directly or after interventions targeting inflammation, by vaccination to boost T-cell repertoires or by adoptive T-cell transfer. The majority of patients will subsequently develop acquired resistance followed by immune escape; this will lead to the next cycle of treatments incorporating multi-modal biomarkers (e.g., based on microbiome phenotype, cfDNA, circulating cytokine levels) and perhaps NK cells recognizing loss of MHC class I by neoplastic cells, thus rendering them invisible to T cells. Cytotoxic treatments, such as with NK cells, standard CTX/RT, or oncolytic viruses, will release neo-antigens that can be used to generate the next round of effector T cells. To this latter point, we must fully understand the rules of T-cell priming in vivo in humans, identify the most effective ways to utilize DCs for priming, and develop strategies for mobilizing the naive T-cell repertoire from the thymus in adults (). In later rounds of therapy, the scope of neo-antigens will likely be broadened as, in addition to somatic mutations, neo-antigens can be generated via epigenetic and post-translational regulation. Last but not least, the role of Tregs, so well established in murine cancer, will need to be redefined in humans. Resolving all of these challenges will surely keep us busy for a long while.