From Suppression to Activation: Rewiring Innate Immunity in Cancer Therapy

The tumor microenvironment (TME) is a complex and dynamic ecosystem in which innate immune cells play a pivotal role in shaping cancer progression and therapeutic outcomes. Traditionally viewed as immunosuppressive, innate immune populations, such as tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), monocytes, and eosinophils, have often been associated with tumor growth, metastasis, and resistance to therapy. However, recent advances in immunoengineering and single-cell profiling have revealed their remarkable plasticity and potential as powerful effectors of anti-tumor immunity. A paradigm shift is underway, transitioning from efforts to non-specifically deplete or suppress these cells toward strategies aimed at reprogramming or activating them for therapeutic benefit. Novel approaches such as macrophage-activating drugs, neutrophil-targeting biologics, and genetically engineered CAR-macrophages and CAR-neutrophils are ushering in a new era of innate immunotherapy. This Special Topic seeks to explore these exciting developments and foster a deeper understanding of how rewiring innate immunity can unlock new frontiers in cancer therapy.This Research Topic aims to bring together cutting-edge research and expert perspectives focused on the activation and reprogramming of innate immune cells in cancer therapy. By showcasing recent advancements in neutrophil- and macrophage-targeted therapies, including emerging strategies such as CAR-macrophages, CAR-neutrophils, bispecific and multispecific antibodies with or without payloads, and combination immunotherapies, we aim to redefine the functional roles of myeloid cells in the TME. The goal is to highlight both the promise and the challenges of turning historically suppressive cells into potent anti-tumor agents. We also seek to bridge the gap between basic immunology, translational research, and clinical application by inviting studies on the molecular mechanisms of innate immune cell plasticity, preclinical validation of novel therapies, and early-phase clinical trials. Through this collection, we hope to inspire novel therapeutic concepts and promote collaborative, interdisciplinary approaches to overcome the immune resistance often seen in solid tumors.We invite original research articles, reviews, mini-reviews, perspectives, and opinion pieces that address the rewiring of innate immunity for cancer therapy. Submissions may include, but are not limited to, the following topics: • Mechanistic studies on the plasticity and reprogramming of TAMs, TANs, monocytes, neutrophils, MDSCs, and eosinophils in the TME • Development and evaluation of neutrophil- or macrophage-activating agents • Engineering and therapeutic application of CAR-macrophages/monocytes and CAR-neutrophils • Combination strategies involving innate immune modulation and existing immunotherapies (e.g., checkpoint inhibitors) • Preclinical and early clinical data on innate immune-targeted cancer therapies • Innovative tools and technologies for profiling and manipulating myeloid immune cells in vivo Authors are encouraged to submit interdisciplinary work that integrates immunology, oncology, bioengineering, and systems biology. All manuscripts will undergo rigorous peer review and should contribute to advancing the current understanding or treatment potential of innate immune-based cancer therapies. Topic editors: Mokarram Hossain, Zhutian Zeng Source: https://www.frontiersin.org/research-topics/72926/from-suppression-to-activation-rewiring-innate-immunity-in-cancer-therapy