Phenotypic Plasticity of Tumor-Associated Neutrophils in the Solid Tumor Microenvironment and Emerging Interventions

Tumor-associated neutrophils (TANs) are a highly dynamic and key component of the tumor microenvironment (TME) in solid tumors and are characterized by an exceptional degree of phenotypic plasticity and functional heterogeneity. TANs play an important role in the control of tumor evolution, metastasis, immune suppression, and therapeutic resistance. The heterogeneity of TANs is reflected in their protumor (TAN2) or antitumor (TAN1) behaviors, which depend on the signals provided by the TME, such as cytokines, metabolism, and epigenetic changes. New developments in single cell RNA sequencing and spatial transcriptomics have also revealed a range of TAN subpopulations in addition to the original TAN1/TAN2 dichotomization. Protumor TANs aid in angiogenesis, metastasis, extracellular matrix remodeling, and immunosuppression, and anti-tumor TANs play a role in cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), antigen presentation, and the promotion of adaptive immunity. This review provides a summary of the phenotypic plasticity of TANs, their dual function in solid tumors, and the underlying mechanisms. In addition, this review explains the therapeutic approaches using TANs in cancer therapy, such as blocking pro-tumor actions, reconfiguring TANs to an antitumor phenotype, restructuring the immune microenvironment, and creating novel advanced nanomedicines. This article highlights the importance of focusing on neutrophils and improving the management of solid tumors by combining their biological properties with a discussion of the possible mechanisms and limitations connected to neutrophil heterogeneity and plasticity. In addition, a fresh perspective for interpreting basic neutrophil studies in clinical practice is provided.