A self-assembled metabolic regulator reprograms macrophages to combat cytokine storm and boost sepsis immunotherapy

Background

Sepsis is a fatal syndrome characterized by life-threatening organ dysfunction originating from a chaotic and unchecked innate immune response to infection. Notably, macrophages are the master regulators of inflammation and immune homeostasis. However, macrophages become hyperactivated in septic conditions, flooding the system with pro-inflammatory cytokines that fuel immune dysregulation and precipitate cascading organ failure. Especially, sepsis-induced acute lung injury has become a focus of contemporary research. Therefore, the immunomodulatory capacity and polarization of macrophages are intricately associated with the onset and progression of sepsis.

Macrophage metabolism is crucial in this polarization because the shift from oxidative phosphorylation to glycolysis powers the inflammatory M1 phenotype during sepsis. This metabolic shift enables macrophages to meet the bioenergetic and biosynthetic demands of the immune surge. Meanwhile, multidimensional regulatory pathways of macrophage polarization and function, including immunometabolism, epigenetics, and immune checkpoints, have been clearly elucidated. Consequently, targeting glycolysis represents an innovative therapeutic strategy for manipulating macrophage function and potentially reprogramming the inflammatory response to mitigate sepsis-induced damage.

Itaconate, a metabolite deeply embedded in the macrophage metabolism, has garnered significant attention due to its regulatory role. Studies have demonstrated that itaconate suppresses the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation. Moreover, its derivative 4-octyl itaconate (4-OI) shows considerable efficacy in attenuating sepsis by blocking the stimulator of interferon genes (STING) innate immunity pathway. However, hyperactive glycolysis in macrophages can reduce the anti-inflammatory effects of itaconate during sepsis, potentially restoring a pro-inflammatory profile. Thus, the precise modulation of glycolysis could elucidate the full therapeutic potential of itaconate.

Research Progress

In order to address the challenge of sepsis treatment through immune metabolic modulation, the research team led by Prof. Gaofei Wei at the Institute of Medical Research, Northwestern Polytechnical University (NPU), has reported a novel sepsis therapy strategy based on immunometabolic regulation. The study revealed a key coordination mechanism between glycolysis and the STING pathway in macrophage inflammatory responses. Building upon this, the team developed a self-assembling prodrug named LDO, which simultaneously targets glycolysis and STING signaling. LDO effectively reprograms macrophage polarization, alleviates CCL2-mediated cytokine storms and acute lung injury, and significantly improves the survival rate in sepsis animal models (Fig. 1). This study proposes an innovative inflammation-regulation strategy based on immunometabolic intervention, providing both theoretical and practical foundations for the translational application of metabolically active immunomodulatory small molecules in sepsis therapy.

To investigate the metabolic reprogramming of macrophages during sepsis, the researchers employed a cecal ligation and puncture (CLP) mouse model. Transcriptomic analysis of macrophages from CLP-induced sepsis models revealed that HK2-mediated glycolysis and STING-dependent signaling are closely associated with disease severity, suggesting that co-targeting these pathways could help regulate macrophage immune imbalance and suppress early inflammatory responses. Based on this, the authors developed a novel self-assembling immunomodulator, LDO, which effectively inhibited both glycolysis and STING signaling. In both CLP and LPS-induced sepsis models, LDO significantly alleviated lung inflammation, tissue damage, and immune cell infiltration. Mechanistic studies showed that LDO suppressed inflammatory signaling and reprogrammed macrophage gene expression, particularly by modulating cytokine and chemokine interactions. Moreover, LDO promoted macrophage polarization from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 state and downregulated CCL2 expression, thereby mitigating the cytokine storm characteristic of sepsis.

Future Prospects

This study highlights the critical role of HK2-mediated glycolysis and STING signaling in macrophage-driven inflammation during sepsis. The dual-targeting strategy of LDO offers a promising approach to modulate immune metabolism and alleviate cytokine storms. The regulation of chemokine signaling, particularly the CCL2 axis, opens new avenues for selectively modulating immune cell trafficking and polarization in inflammatory diseases. Future studies could investigate the synergistic potential of LDO in combination with other immunotherapies, such as immune checkpoint inhibitors or anti-cytokine agents, to further enhance therapeutic efficacy. Additionally, exploring its applicability in other inflammatory diseases and in combination with existing therapies may broaden its therapeutic scope. Overall, this work lays a foundation for developing metabolism-based immunotherapies for sepsis and related disorders.