Metabolic activation using fructose-1,6-bisphosphate microparticles of non-virally LNP-generated CAR-macrophages induces anti-tumor immune responses.

While chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable clinical efficacy in hematological malignancies, its impact on solid tumors remains limited, largely due to insufficient T cell infiltration into the tumor microenvironment (TME). In contrast, macrophages are inherently recruited to the TME, offering a promising platform for cell-based immunotherapy. However, the nutrient-deprived conditions within the TME drive macrophages toward an immunosuppressive, tumor-promoting phenotype, thereby constraining their therapeutic potential. Here, we report a metabolic accelerating strategy designed to potentiate the anti-tumor activity of CAR-engineered macrophages (CAR-macs) by increasing their glycolytic capacity. We demonstrate that pre-treatment of CAR-macs with microparticles generated from fructose 1,6-bisphosphate (F16BP) can augment glycolytic flux and promote pro-inflammatory polarization. In a murine lymphoma solid tumor model, this approach significantly enhances anti-tumor immune cell responses and demonstrates that the CAR-macs are able to home to the tumor site. Our findings establish a novel paradigm in CAR macrophage-based immunotherapy, demonstrating that metabolic reprogramming can overcome the immunosuppressive TME and substantially improve therapeutic efficacy against solid tumors.