Macrophages at the interface of the co-evolving cancer ecosystem

Macrophages are versatile and heterogeneous innate immune cells undertaking central functions in balancing immune responses and tissue repair to maintain homeostasis. This plasticity, once co-opted by malignant outgrowth, orchestrates manifold reciprocal interactions within the tumor microenvironment, fueling the evolution of the cancer ecosystem. Here, we review the multilayered sources of influence that jointly underpin and longitudinally shape tumor-associated macrophage (TAM) phenotypic states in solid neoplasms. We discuss how, in response to these signals, TAMs steer tumor evolution in the context of natural selection, biological dispersion, and treatment resistance. A number of research frontiers to be tackled are laid down in this review to therapeutically exploit the complex roles of TAMs in cancer. Building upon knowledge obtained from currently applied TAM-targeting strategies and using next generation technologies, we propose conceptual advances and novel therapeutic avenues to rewire TAM multifaceted regulation of the co-evolving cancer ecosystem.

Automated summary

Macrophages play versatile and heterogeneous roles in innate immunity, maintaining immune responses and tissue repair. However, when co-opted by malignant outgrowth, macrophages can contribute to tumor evolution within the tumor microenvironment. This review explores the sources of influence that shape tumor-associated macrophage (TAM) phenotypic states in solid neoplasms and discusses how TAMs steer tumor evolution in response to these signals. The authors propose new therapeutic approaches to exploit the complex roles of TAMs in cancer.