Lactate-Induced Protein Modification Impairs Natural Killer Cell Defense Against Cancer

A recent study published in Nature Immunology has shed light on how lactate within the tumor microenvironment (TME) can weaken the immune system's natural defenses against cancer. Led by Prof. Wang Yi and Wei Haiming from the University of Science and Technology of China, in collaboration with Prof. Ding Chen's team from Fudan University, researchers uncovered that high levels of lactate promote a specific protein modification called lysine lactylation (Kla) in natural killer (NK) cells. This modification hampers NK cells' ability to combat tumors effectively.

NK cells are crucial components of cancer immunotherapy due to their rapid response, broad-spectrum activity, and low toxicity. Yet, the metabolic environment within tumors often suppresses their function. The team discovered that elevated lactate in the bone marrow TME induces Kla in NK cells, leading to mitochondrial fragmentation, disrupted NAD+ homeostasis, and ultimately suppressed anti-tumor activity.

To counteract this, scientists explored a novel intervention involving the supplementation of nicotinamide riboside, a precursor to NAD+, alongside honokiol, a SIRT3 activator. This combination reduces Kla levels by enhancing the activity of SIRT3, an enzyme responsible for removing lactylation. The intervention restored NK cells' cytotoxic functions by modulating the Kla of the kinase ROCK1, which affects mitochondrial dynamics through the phosphorylation of the fission protein DRP1. This prevents mitochondrial fragmentation and reinvigorates NK cell activity.

This groundbreaking research elucidates a new mechanism whereby lactate impairs NK cell-mediated tumor clearance via Kla. It also paves the way for innovative strategies to enhance NK cell-driven immunotherapy, boosting their capacity to fight cancer in metabolically hostile environments.

The findings hold significant potential for developing targeted treatments to overcome TME-induced immunosuppression, offering hope for improved cancer therapies in the future.

Source: medicalxpress.com