The Q for immune evasion in HCC: ER stress in myeloid cells

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. In most cases, HCC develops in an already perturbed liver microenvironment with pre-existing liver cirrhosis and tissue remodelling. Once a tumour nodule evolves, a complex ecosystem comprising tumour, immune, structural cells and extracellular matrix develops and forms the so-called tumour microenvironment (TME).1 This TME is shaped by distinct metabolic networks particularly driven by metabolic reprogramming of tumour cells, which supports their function, as one of the hallmarks of cancer.2 For example, in many cancer types, tumour cells mostly depend on glucose consumption for their energy supply, leading to lactate production and acidic conditions in the TME even with enough oxygen (Warburg effect).3 In addition, tumour cells also heavily rely on the amino acid glutamine (single letter code: Q) for their nucleotide biosynthesis and thus proliferation as well as for lipid biosynthesis and energy supply.4 On the other hand, similar metabolic demands also apply for highly active and proliferative immune cells such as T cells and macrophages, cell populations depending on glucose and glutamine for cell function and proliferation.5 Consequently, harsh conditions with low nutrient availability, metabolic competition and an acidic milieu in the TME emerge and impair immunosurveillance thus fuelling immune evasion.6 Yet, the exact mechanisms of how metabolic reprogramming of tumour cells results in immune evasion remain only partly understood. In Gut, Yang et al addressed this question in a preclinical setting using mouse models and employing human samples.7 The study was based on the observation, that in …