According to the world health statistics 2024, cancer accounts for over 20 million new diagnoses annually and results in more than 10 million deaths each year, remaining one of the leading causes of death worldwide [1]. In tumor progression and tumor therapy, the tumor immune microenvironment (TIME) with tumor-associated macrophages (TAMs) as key components, plays a crucial role [2,3]. TAMs exhibiting M2 phenotypes facilitate an immunosuppressive environment, closely correlating with poor prognoses in cancers such as hepatocellular carcinoma, pancreatic ductal adenocarcinoma, and breast cancer. To address such issue, therapeutic strategies have been developed to polarize M2 TAMs to M1 phenotypes which secrete pro-inflammatory factors to generate antitumor immune responses and inhibit tumor growth via reactive oxygen species (ROS), nitrogen oxide (NO), and tumor necrosis factor α (TNF-α) [[4], [5], [6]]. Additionally, macrophages exhibit substantial heterogeneity in biological functions beyond the classical M1/M2 dichotomy, including angiogenesis regulation, matrix remodeling, antigen presentation, metabolic crosstalk, and therapy resistance [7]. For this reason, polarizing TAMs has garnered extensive attention in tumor immunotherapy.

Nanomedicines, which are widely utilized in immunotherapy [[8], [9], [10], [11], [12], [13]], have emerged as powerful tools for repolarizing TAMs by delivering therapeutic agents, including small-molecule inhibitors, nucleic acids, and cytokines, with improved specificity and reduced systemic toxicity [[14], [15], [16]]. Unlike small molecule drugs that distribute indiscriminately across tissues, nanoparticle delivery systems accumulate at tumor site via enhanced permeability and retention (EPR) effect and internalized by macrophages via natural phagocytosis to achieve TAMs targeting delivery, of which the efficiency could be further improved by optimizing physicochemical properties [[8], [9], [10],14]. Furthermore, engineering nanoparticles physicochemical properties has been gradually explored that can repolarize TAMs individually in absence of therapeutic agents. Size [17,18], morphology [19], surface properties, and stiffness [[20], [21], [22], [23]] of nanoparticles can be engineered to polarize macrophages, thus improving the efficacy of immunotherapy. Nevertheless, the mechanism of nanoparticles with distinct physicochemical properties polarizing macrophages remains poorly understood. To date, few studies have elaborated the specific physicochemical parameters of nanoparticles designed for enhanced immunotherapy by polarizing TAMs.

This review systematically summaries the influence of physicochemical properties of nanoparticles on macrophage polarization and delves into the intrinsic crosstalk between the molecular mechanisms of biochemical and mechanical signaling pathways (Fig. 1). Additionally, this review aims to stimulate new strategies for precise regulation of macrophage phenotypes by modulating the physicochemical properties of nanoparticles to achieve anticipative biological functions. Moreover, specific immune effect or multiple immune functions of small molecule drugs can be enhanced or achieved synergistically after loading by subtly designed nanoparticles. Ultimately, by taking full advantages of nanoparticle physicochemical properties in tumor targeting drug delivery, the immunotherapy outcomes in varied tumor types will gain great improvement.