Novel Methods to Overcome Acquired Resistance to Immunotherapy

Abstract

The remarkable success of immunotherapy, including immune checkpoint blockade therapy (ICBT) in clinical settings, such as in melanoma patients and patients with DNA mismatch repair deficient tumors, has shifted the paradigm of cancer treatment. However, immunotherapy continues to face major challenges in controlling malignancy due to both intrinsic and acquired resistance mechanisms. Here, we discuss the mechanisms by which cancer immunotherapy has harnessed the immune system to target tumor progression, as well as the mechanisms of acquired resistance to immunotherapy. We also describe novel approaches in overcoming this resistance, with a particular focus on ICBT. We explore mechanisms by which tumor-intrinsic cues, tumor microenvironmental factors, and the host microbiome might impact the efficacy and resistance often seen during ICBT. Furthermore, we introduce technologies that will identify biomarkers from mouse and human models to predict clinical benefits for ICBT in cancer patients and promising emerging strategies to overcome ICBT resistance.