Core Viewpoint - The study reveals that macrophage PD-1 plays a critical role in the intersection of immune checkpoint blockade, energy expenditure, and metabolic dysfunction, providing a new theoretical basis for combating metabolic diseases induced by immune checkpoint inhibitors and high-fat diets [7]. Group 1: Research Findings - The research indicates that anti-PD-1 antibodies target macrophage PD-1, reducing energy expenditure without affecting food intake, thereby increasing susceptibility to obesity and systemic metabolic disorders induced by high-fat diets [4]. - The mechanism involves lipopolysaccharide (LPS) activating Unc-51-like autophagy activating kinase-1 (ULK1) in an mTOR-dependent manner, which phosphorylates PD-1 at the Thr250 site, preventing its ubiquitination and degradation by FBXO38 [4][8]. - Phosphorylated PD-1 interacts with IRE1α, inhibiting its phosphorylation and thereby suppressing inflammation driven by endoplasmic reticulum stress [4][8]. Group 2: Implications - The findings suggest that targeting IRE1α-XBP1 may offer a potential strategy to counteract metabolic dysfunction induced by immune checkpoint inhibitors [8]. - The study's insights into the dual role of macrophage PD-1 could lead to new therapeutic approaches for managing metabolic disorders associated with cancer treatments [7].

Core Viewpoint - The study reveals that Itaconate, contrary to its traditional anti-inflammatory perception, promotes inflammatory responses in tissue-resident alveolar macrophages, exacerbating acute lung injury [2][9]. Group 1: Effects of Itaconate - Itaconate enhances the production of pro-inflammatory cytokines and activates the NLRP3 inflammasome in alveolar macrophages [4][7]. - Pre-treatment with Itaconate worsens LPS-induced lung tissue damage, while knocking out ACOD1 significantly improves survival rates in acute lung injury mouse models [2][6]. Group 2: Comparison with Bone Marrow-Derived Macrophages - The response of bone marrow-derived macrophages (BMDM) to Itaconate is opposite to that of tissue-resident alveolar macrophages, indicating the critical role of the pulmonary microenvironment in shaping macrophage immune metabolism [5][10]. Group 3: Itaconate Derivatives - Unlike natural Itaconate, its derivatives, dimethyl itaconate (DI) and 4-octyl itaconate (4OI), can inhibit the inflammatory response in alveolar macrophages [4][7]. Group 4: Implications for Clinical Treatment - The findings suggest that further research is necessary before considering Itaconate for clinical applications in treating inflammatory diseases, given its unexpected pro-inflammatory role in tissue-resident alveolar macrophages [9][10].