ACT001 Suppresses the Malignant Progression of Small‐Cell Lung Cancer by Inhibiting Lactate Production and Promoting Anti‐Tumor Immunity

TL;DR

ACT001 slows the growth of small-cell lung cancer by reducing lactate and boosting the immune response against the tumor.

Contribution

ACT001 is a novel compound that targets PGK1 to inhibit lactate production and improve the tumor immune environment in SCLC.

Findings

ACT001 reduced lactate accumulation and M2 macrophage polarization in SCLC.

Micheliolide from ACT001 covalently modified PGK1, suppressing its activity and altering its distribution.

ACT001 showed anti-tumor effects in vitro and in vivo with no systemic toxicity.

Abstract

Improving the “cold” tumor immune microenvironment (TIME) of small‐cell lung cancer (SCLC) represents a promising therapeutic approach. The metabolite lactate plays a crucial role in shaping the immune‐cold tumor microenvironment (TME) and facilitating tumor progression. Phosphoglycerate kinase 1 (PGK1) is a key enzyme involved in tumor lactate metabolism. This study demonstrates that ACT001 improves the TIME of SCLC through inhibiting lactate production by targeting PGK1.

The cytotoxic effects of ACT001 on SCLC cell lines NCI‐H1688 and NCI‐H446 were evaluated using MTT assay, clone formation, EdU incorporation, wound healing, and invasion assays. To elucidate the mechanism of action of ACT001, proteomic techniques, pull‐down assays, LC–MS/MS, surface plasmon resonance, immunofluorescence, lactate generation, glucose uptake, and western blot assays were conducted. A xenograft model was used to assess the in vivo anti‐tumor activity of ACT001.

ACT001 inhibited the proliferation, invasion, and metastasis of SCLC both in vitro and in vivo. Additionally, it reduced lactate accumulation and M2 macrophage polarization. Mechanistically, ACT001 released micheliolide, which covalently modified Cys316 of PGK1 under physiological conditions. This suppressed PGK1 activity and restored the distribution of PGK1 in mitochondria and the cytoplasm under hypoxic conditions.

ACT001 inhibits the malignant progression of SCLC by suppressing lactate production, modulating macrophage polarization, and restraining tumor metastasis through PGK1 targeting.

ACT001, exerted anti‐tumor activity, inhibited lactate production and promoted anti‐tumor immunity by targeting PGK1, showing no observable systemic toxicity in vivo.

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