Beyond the mutation: integrating radiogenomics, epigenetics, and immune signatures to overcome therapeutic resistance in CNS tumors: a narrative review

Abstract

Despite advancements in the field of cancer treatment, its efficacy in tackling central nervous system (CNS) tumors – glioblastomas – remains blunted. This review explores the multifactorial reasons behind these tumors’ resistance to immunotherapeutic strategies, with emphasis on the role of the tumor microenvironment, low mutational burden, and immune exclusion. Emerging immune phenotypes – such as inflamed, excluded, and desert types – have varying contributions to the degree of response. Recent advances in immune profiling, including single-cell RNA sequencing and spatial transcriptomics, have begun to pave the way for a deeper understanding of the immunosuppressive architecture of these tumors, revealing the involvement of tumor-associated macrophages, myeloid-derived suppressor cells, and T-regulatory populations. Additionally, we examine the impact of tumor-nerve crosstalk, T-cell exhaustion, and the limited ability of PD-L1 and tumor-mutation burden as predictive markers. The review also highlights the newfound therapeutic strategies – including CAR-T cell therapy and bispecific antibodies – that aim to overcome immune resistance. By integrating insights from immunogenomics, epigenetics, and radiogenomics, we propose a framework for understanding and potentially reversing immune resistance in CNS tumors. This review highlights the urgent need to develop specific, biomarker-informed approaches that would aim to improve outcomes in this domain of neuro-oncology.