The efficacy of radiotherapy, a mainstay of cancer treatment, is strongly influenced by both cellular and non-cellular features of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are a heterogeneous population within the TME and their prevalence significantly correlates with patient prognosis in a range of cancers. Macrophages display intrinsic radio-resistance and radiotherapy can influence TAM recruitment and phenotype. However, whether radiotherapy alone can effectively “reprogram” TAMs to display anti-tumor phenotypes appears conflicting. Here, we discuss the effect of radiation on macrophage recruitment and plasticity in cancer, while emphasizing the role of specific TME components which may compromise the tumor response to radiation and influence macrophage function. In particular, this review will focus on soluble factors (cytokines, chemokines and components of the complement system) as well as physical changes to the TME. Since the macrophage response has the potential to influence radiotherapy outcomes this population may represent a drug target for improving treatment. An enhanced understanding of components of the TME impacting radiation-induced TAM recruitment and function may help consider the scope for future therapeutic avenues to target this plastic and pervasive population.

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An immunosuppressive microenvironment causes poor tumour T-cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumours is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identify complement receptor C5aR1 as a druggable target which when inhibited improves radiotherapy even in tumours displaying immunosuppressive features and poor CD8+ T-cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we find that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumour-cell specific functions. C5aR1 targeting results in increased NF-κB-dependent apoptosis specifically in tumours and not normal tissues; indicating that in malignant cells, C5aR1 primarily regulates cell fate. Collectively, these data reveal that increased complement gene expression is part of the stress response mounted by irradiated tumours and that targeting C5aR1 can improve radiotherapy even in tumours displaying immunosuppressive features.