Therapeutics that modulate immune cell metabolism have achieved major success in cancer research. [[1], [2], [3], [4]] Notably, activating innate immune cells such as dendritic cells (DCs) and macrophages (Mɸs) requires the modulation of metabolic intermediates and metabolic pathways. [[5], [6], [7], [8], [9]] The accumulation of metabolic intermediates has the potential to regulate immune responses and could play a role in disease progression, such as inflammation caused by tumors.9 For example, cancer vaccines activate DCs and tumor-associated Mɸs (TAMs) by modulating their energy metabolism (e.g., glycolysis, glutaminolysis, Krebs cycle). [10] Immune cells' metabolic demands change along with changes in their activation status. [11,12] It has been observed that immune-cell metabolism adapts to match these demands, metabolically shifting through the increased expression of nutrient transporters and oxidative phosphorylation pathways. [13] For example, when activated DCs and Mɸs upregulate glucose and glutamine transporters, this enables downstream signaling and the production of pro-inflammatory proteins. [14,15]

Like activated immune cells, cancer cells also upregulate glucose and glutamine transporters for proliferation and survival. In fact, hyperactivation of cancer-cell metabolism is a direct result of the modulation of intracellular signaling pathways that are disrupted by mutated oncogenes and tumor-suppressor genes. [16] Cancer cells preferentially uptake and convert glucose into lactate even in the presence of sufficient oxygen, known as the Warburg effect. [17,18] Recent studies observed that glutamine is an essential bioenergetic and anabolic substrate for many cancer cell types. [16] Cancer cells exhibiting aerobic glycolysis rely on glutamine as well as glucose as the carbon source. [19,20] Glutamine is used to provide intermediates of the Krebs cycle to feed biosynthetic pathways as precursors. [21] Therefore, cancer cells are dependent on glutamine for survival and proliferation. [22,23] Cancer cells have accelerated energy metabolism, which has been exploited as a target for various therapeutic studies. [24,25] In clinical trials, blocking the glutaminase pathway has been used to treat melanoma, squamous cell carcinoma, and other solid tumors. [[26], [27], [28], [29]]

Glutaminolysis feeds into the Krebs cycle and generates metabolites such as succinate. [5] Succinate is associated with an inflammatory response in innate immune cells. [30,31] Also, succinate is synthesized within the mitochondria and converted to fumarate in the TCA cycle. [32] The succinate receptor SUCNR1 is present on the cell surface and expressed in myeloid cells such as DCs and Mɸs. [32,33] Recent studies suggest that, when succinate accumulation activates SUCNR1, it increases inflammatory cytokine production in both human and mouse DCs. [33] Moreover, succinate accumulation results in increased IL-1β secretion, an effect that was lost in SUCNR1-deficient mice. [34,35] Succinate's inflammatory effect can thus be used to effectively modulate immune-cell metabolism and generate pro-inflammatory immunotherapy. [36] Phagocytes (DCs and Mɸs) can sample foreign material like synthetic particles. [37,38] Therefore, particles that are able to deliver metabolites such as succinate to these phagocytic cells may be able to modulate immune-cell metabolism. [38,39]

This study describes an immunometabolism strategy based on the sustained release of succinate from biomaterials, which incorporate succinate in the polymer's backbone (Fig. 1a). These succinate-based polymers allow phagocytes to perform their metabolic function in the presence of chemotherapeutics. Sustained release of succinate not only modulates the metabolism of innate immune cells but also induces a pro-inflammatory phenotype in these cells, resulting in effective cancer immunotherapy. This vaccine formulation was tested in young melanoma mouse model.