Reprogramming the tumour microenvironment: Emerging strategies to overcome immunotherapy resistance

Abstract Background The advent of cancer immunotherapy, particularly immune checkpoint inhibitors, has revolutionised the treatment landscape for many malignancies. However, a significant proportion of patients exhibit primary, adaptive, or acquired resistance to these therapies, limiting their broad clinical benefit. Tumour microenvironment (TME), a complex and dynamic ecosystem of cancer cells, immune cells, stromal cells and extracellular matrix, has emerged as a critical determinant of immunotherapy response and a major driver of resistance. Main body This review provides a comprehensive overview of the intricate mechanisms by which the TME fosters an immunosuppressive milieu, thereby impeding effective anti‐tumour immunity. We delineate the key cellular and molecular components of the TME that contribute to immunotherapy resistance, including tumour‐associated macrophages, myeloid‐derived suppressor cells, regulatory T cells, and cancer‐associated fibroblasts. We then discuss the diverse and innovative strategies being developed to reprogram the TME and overcome these resistance mechanisms. These emerging approaches include targeting immunosuppressive cell populations, modulating tumour metabolism, epigenetic reprogramming, normalising the tumour vasculature and employing engineered cell therapies such as chimeric antigen receptor T cells and oncolytic viruses. The potential of combination therapies to synergistically dismantle the immunosuppressive TME is also explored. Conclusion Reprogramming the TME represents a paradigm shift in cancer treatment, moving beyond direct tumour cell targeting to modulate the entire tumour ecosystem. While significant challenges remain, including TME heterogeneity and the need for predictive biomarkers, the strategies discussed herein hold immense promise for overcoming immunotherapy resistance and improving patient outcomes. A deeper understanding of the complex interplay between the tumour and its microenvironment will be crucial for the development of next‐generation, personalised immunotherapeutic strategies.