In this issue of Cancer Cell, Medler et al. demonstrate that fibrinolytic enzyme-mediated generation of complement C5a reprograms tumor-infiltrating C5aR1+ macrophages into an immunosuppressive phenotype that dampens CD8+ T cell responses during squamous carcinogenesis. C5aR1 blockade combined with chemotherapy offers a promising immunomodulatory strategy for treating squamous cell carcinoma.
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