Hypermutable cancers create opportunities for the development of various immunotherapies, such as immune checkpoint blockade (ICB) therapy. However, emergent studies have revealed that many hypermutated tumors have poor prognosis due to heterogeneous tumor antigen landscapes, yet the underlying mechanisms remain poorly understood. To understand the mechanisms that govern the responses to therapies, we develop mathematical models to explore the impact of combining chemotherapy and ICB therapy on heterogeneous tumors. Our results uncover how chemotherapy reduces antigenic heterogeneity, creating improved immunological conditions within tumors, which, in turn, enhances the therapeutic effect when combined with ICB. Furthermore, our results show that the recovery of the immune system after chemotherapy is crucial for enhancing the response to chemo-ICB combination therapy.
Keywords: chemo‐immunotherapy; immune checkpoint blockade; mathematical modeling; neoantigen heterogeneity; treatment strategy.
© 2025 The Author(s). Quantitative Biology published by John Wiley & Sons Australia, Ltd on behalf of Higher Education Press.