Nanoagonist‐mediated spatiotemporal reprogramming of macrophage phenotypes to potentiate tumor immunotherapy

Tumor‐associated macrophages (TAMs) as the most abundant and dominant immune cells in the tumor microenvironment (TME) exhibit pronounced phenotypic plasticity and a typical Janus role in both tumor suppression and promotion. In most solid tumors, TAMs predominantly differentiate into an M2‐like phenotype, which suppresses adaptive immunity and promotes tumor metastasis. It is closely related to the therapeutic resistance and poor patient prognosis. Recently, targeted TAM modulation, which is focused on the reprogramming of TAMs toward a pro‐inflammatory, antitumor M1 phenotype, has emerged as an extremely promising immunotherapeutic strategy. However, the therapeutic efficacy of current pharmacological approaches remains suboptimal, owing to their insufficient tumor specificity, dose‐limiting systemic toxicity, poor intratumoral drug delivery, as well as inherent instability and reversibility of reprogrammed macrophage phenotypes within the persistently immunosuppressive TME. Fortunately, nanoparticle‐based immune agonists have provided versatile platforms with selective targeting, spatiotemporal control, and prolonged immunomodulatory effects, offering a promising strategy to precisely reprogram TAM phenotypes. This review systematically summarizes the molecular mechanisms associated with TAM polarization, and particularly focuses on the major regulatory pathways including nuclear factor‐κB (NF‐κB), Janus kinase signal transducer and activator of transcription (JAK‐STAT), cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING), mitogen‐activated protein kinase (MAPK), metabolic reprogramming, and their coordinated interactions. It further provides a comprehensive overview of recent advances in nanoagonist‐based strategies that intervene in these pathways to reprogram TAMs, critically discussing their therapeutic potential, current limitations, and translational prospects. Collectively, this work provides an integrated mechanistic and technological framework to guide the rational design of macrophage‐targeted nanomedicine for tumor immunotherapy.