Targeting macrophages: a novel avenue for cancer drug discovery

Introduction: Tumor-associated macrophages (TAMs) make up a significant portion of the tumor microenvironment. Emerging clinical evidence indicate that cytokines present in the tumor microenvironment influence TAMs to play an immunosuppressive role by acquiring a pro-tumoral phenotype. However, TAMs are inherently plastic cells that can be phenotypically reprogrammed to elicit an anti-tumoral response. Therapeutic strategies that focus on targeting TAMs have opened new avenues for drug discoveries. Areas covered: This review discusses recent developments in TAM targeted immunotherapy in both preclinical and clinical settings. This article highlights the potential signaling pathways that can be targeted for macrophage reprogramming and discusses the progress of current clinical trials involved in TAMs targeting. Novel nanoparticle-based drug delivery strategies involved in macrophage-based cancer therapeutics and diagnostics are also discussed. Expert opinion: TAM targeted therapies have limited success in clinics due to reasons such as insufficient inhibition of signaling pathways, lower drug accumulation in the tumor, activation of feedback signaling pathways that induce resistance to monotherapies and systemic dose-related toxicities. Nanoparticle-based delivery platforms could overcome these challenges since they enable encapsulation of multiple drugs that target different signaling pathways and enhance intratumoral delivery and can enable delivery of imaging agents.