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Hepatocellular carcinoma (HCC) is one of the cancers that seriously threaten human health. Immunotherapy serves as the mainstay of treatment for HCC patients by targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) axis. However, the effectiveness of anti-PD-1/PDL1 treatment is limited when HCC becomes drug-resistant. Tumor-associated macrophages (TAMs) are an important factor in the negative regulation of PD-1 antibody targeted therapy in the tumor microenvironment (TME). Therefore, as an emerging direction in cancer immunotherapy research for the treatment of HCC, it is crucial to elucidate the correlations and mechanisms between TAMs and PD-1/PD-L1-mediated immune tolerance. This paper summarizes the effects of TAMs on the pathogenesis and progression of HCC and their impact on HCC anti-PD-1/PD-L1 immunotherapy, and further explores current potential therapeutic strategies that target TAMs in HCC, including eliminating TAMs in the TME, inhibiting TAMs recruitment to tumors and functionally repolarizing M2-TAMs (tumor-supportive) to M1-TAMs (antitumor type). [ABSTRACT FROM AUTHOR]

Nitro-fatty acids (NO2-FAs) are a class of bioactive lipids that mediate metabolic, anti-oxidative stress, anti-inflammatory, and other signaling actions. Endogenously, NO2-FAs are derived from the non-enzymatic reactions of unsaturated fatty acids with reactive nitrogen species. The electrophilic properties of the nitro group results in NO2-FAs being able to undergo rapid and reversible reactions with biological nucleophiles, such as cysteine and histidine, thus supporting post-translational modifications of proteins. The reactions of NO2-FAs with biological nucleophiles regulate a range of key signaling pathways involved in gene expression responses, enzyme activity, and cellular processes. In disease animal models, NO2-FAs are produced under conditions of inflammation and oxidative stress and play a protective role in a variety of metabolic diseases, which have been associated with anti-atherosclerosis, blood-pressure lowering, and are involved in the regulation of glycolipid metabolism and insulin resistance. Based on these, more clinical studies might find a correlation between NO2-FAs levels and pathophysiology in patients with metabolic diseases. Importantly, NO2-FAs therapeutics are effective in clinical trials. In addition, dietary supplementation with nitrates and unsaturated fatty acids can endogenously increase NO2-FAs levels in mice and humans. These findings support dietary approaches that increase the endogenous levels of NO2-FAs might potentially reduce the risk of metabolic diseases. To identify the specific mechanism of action and therapeutic potential of NO2-FAs, we have summarized the main mechanisms of action of NO2-FAs in metabolic disease progression to provide insights for the development of new therapeutics for metabolic diseases. [ABSTRACT FROM AUTHOR]