Synchronous effects of targeted mitochondrial complex I inhibitors on tumor and immune cells abrogate melanoma...

Area of Science:

• Oncology
• Immunology
• Mitochondrial Biology

Background:

• Metabolic heterogeneity in the tumor microenvironment fuels cancer growth and immune evasion.
• Targeting metabolic pathways offers a potential strategy for cancer therapy.

Purpose of the Study:

• To investigate the effects of mitochondria-targeted complex I inhibitors (Mito-CI) on melanoma growth and the tumor immune microenvironment.
• To elucidate the mechanisms by which Mito-CI exerts anti-tumor activity.

Main Methods:

• Utilized an immune-competent melanoma model system.
• Administered Mito-CI and assessed its impact on tumor cell proliferation, mitochondrial function, and immune cell populations.
• Conducted immune depletion studies to determine the role of T cells.

Main Results:

• Mito-CI decreased mitochondrial oxygen consumption, Akt-FOXO signaling, and cell cycle progression, leading to reduced melanoma proliferation and tumor progression.
• Mito-CI treatment increased the infiltration of activated effector T cells and decreased myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) in vivo.
• Anti-proliferative doses of Mito-CI inhibited MDSC differentiation, viability, and suppressive function, while promoting T cell activation.

Conclusions:

• Targeted inhibition of mitochondrial complex I exhibits dual anti-cancer effects: direct tumor cell growth inhibition and immune microenvironment remodeling.
• Mito-CI represents a promising therapeutic strategy for melanoma by simultaneously targeting tumor metabolism and enhancing anti-tumor immunity.