Cancer immunotherapy strategies are highly effective, though target just a few immunoregulatory pathways, and only benefit a subset of patients; most patients either fail to respond or respond transiently and develop resistance. Mechanisms of primary or secondary resistance are poorly understood, and a variety of immunotherapeutic strategies are in development to harness alternative immune pathways to overcome barriers to clinical response. This meeting will bring together a diverse group of basic, translational and clinical researchers including those from academia, industry and government to cooperatively discuss the mechanistic basis of failed immunotherapy, and novel approaches to activating the immune system, in order to provide insight for future clinical applications of novel approaches and optimal combination therapies. This program will highlight the failures and successes of cancer immunotherapy, explore therapeutic targets within our understanding of host immunity, and discuss challenges of current combination immunotherapy approaches. Alongside a discussion of the status quo—and current barriers—this program will highlight novel approaches to targeting stroma and myeloid cells, novel insights on tumor recognition by multiple lymphoid lineages, and overcoming resistance. We will discuss some of the most promising technologies in development to unravel the complexity of the tumor microenvironment using spatial imaging and AI technology. We will hear from experts on optimal clinical trial design and clinically relevant endpoints. This interdisciplinary meeting will spark new collaborations and inspire new research directions toward identifying novel immunotherapy approaches to benefit patients.