Cancer immunotherapy has improved the survival of a subset of patients by harnessing the power of the immune system to find and destroy malignant cells. The immune system also protects the host by destroying developing premalignant and malignant tumors. Advancing our knowledge of premalignant immunity and immune changes seen in lesions that develop into invasive cancer versus those that regress offers an exciting opportunity to leverage the immune system for immune prevention and immune interception of premalignancy. Understanding the immune environment of premalignant lesions and how chronic inflammation plays a central role in the evolution of premalignancy is essential for developing effective immunoprevention and immune interceptions. Factors such as host genomics and environmental factors that affect premalignant immunity and the outcome of advanced cancers are equally important in determining the response to immunotherapy. The broad use of antibiotics and factors such as obesity can disrupt a healthy gut microbiome and drive chronic inflammation that suppresses preventive immunity or the antitumor immune response required for successful immunotherapy in advanced cancers. Modifiable lifestyle factors such as diet, obesity, smoking, and stress should be considered in designing immune prevention and interception studies, as well as for patients who receive immunotherapy for advanced cancer treatment. Other factors, such as the overall immune health of patients and existing comorbidities, affect both premalignant immunity and response to immunotherapy and, therefore, should be considered in managing patients with or without cancer. The Society for Immunotherapy of Cancer previously developed an overarching manuscript regarding the challenges and opportunities that exist in cancer immunotherapy, and this manuscript serves as an in-depth follow-up regarding the topics of premalignant immunity, immune interception, and immunoprevention, and the impact of the host on responding to immunotherapy.