The field of oncology has transformed with the advent of immunotherapies. The standard of care for multiple cancers now includes novel drugs that target key checkpoints that function to modulate immune responses, enabling the patient's immune system to elicit an effective anti‐tumor response. While these immune‐based approaches can have dramatic effects in terms of significantly reducing tumor burden and prolonging survival for patients, the therapeutic approach remains active only in a minority of patients and is often not durable. Multiple biological investigations have identified key markers that predict response to the most common form of immunotherapy—immune checkpoint inhibitors (ICI). These biomarkers help enrich patients for ICI but are not 100% predictive. Understanding the complex interactions of these biomarkers with other pathways and factors that lead to ICI resistance remains a major goal. Principles of oncophysics—the idea that cancer can be described as a multiscale physical aberration—have shown promise in recent years in terms of capturing the essence of the complexities of ICI interactions. Here, we review the biological knowledge of mechanisms of ICI action and how these are incorporated into modern oncophysics‐based mathematical models. Building on the success of oncophysics‐based mathematical models may help to discover new, rational methods to engineer immunotherapy for patients in the future. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease