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And that's kind of the rub, right

Abbreviations ROS: reactive oxygen species TME: tumor microenvironment Teffs: effector T cells NK: natural killer Tregs: regulatory T cells TAMs: tumor-associated macrophages ETC: electron transport chain NOX: NADPH oxidase COA1: Cytochrome c oxidase assembly factor 1 COA18: Cytochrome c oxidase assembly factor 18 SODs: superoxide dismutases CAT: catalase GPXs: glutathione peroxidases GSH: glutathione PTP1B: protein-tyrosine phosphatase 1B PTEN: phosphatase and tensin homolog mtROS: mitochondrial ROS MAMs: mitochondria-associated ER membranes TCA: tricarboxylic acid ATP: adenosine triphosphate TCR: T cell receptor TILs: tumor-infiltrating lymphocytes RCD: regulated cell death MOMP: mitochondrial outer membrane permeabilization BAX: Bcl-2-associated X protein BAK: Bcl-2 homologous antagonist/killer RIPK1/3: receptor-interacting serine/threonine-protein kinase 1/3 GPX4: GSHglutathione peroxidase 4 MBOAT1 and MBOAT2: membrane-bound O-acyltransferase domain-containing 1 and 2 PUFA-PEs: polyunsaturated phosphatidylethanolamines MUFA-PEs: monounsaturated phosphatidylethanolamines ATG4: autophagy-related gene 4 AMPK: adenosine monophosphate-activated protein kinase ATM: ataxia-telangiectasia mutated CHK2: checkpoint kinase 2 MAPK: mitogen-activated protein kinase GSDMD: gasdermin D mTORC2: mammalian target of rapamycin complex 2 BRCA1: breast cancer gene 1 Nrf2: nuclear factor erythroid 2-related factor 2 KEAP1: Kelch-like ECH-associated protein 1 ATR: Ataxia-Telangiectasia and Rad3-Related PI3K: phosphoinositide 3-kinase mTOR: mechanistic target of rapamycin JNK: c-Jun N-terminal kinase EMT: epithelial-to-mesenchymal transition AP-1: activator protein 1 NF-B: nuclear factor kappa-light-chain-enhancer of activated B cells TGF-: transforming growth factor-beta C/EBP: CCAAT/enhancer-binding protein beta MMPs: matrix metalloproteinases ERK: extracellular signal-regulated kinase SRXN1: sulfiredoxin 1 BTG2: B-cell translocation gene 2 HIF1: hypoxia-inducible factor-1 AML: acute myeloid leukemia LSCs: leukemic stem cells OXPHOS: oxidative phosphorylation MITO: mitochondrial potential FLT3-ITD: fms-like receptor tyrosine kinase 3-internal tandem duplication -KG: -ketoglutarate CLL: Chronic Lymphocytic Leukemia MM: multiple myeloma FAO: fatty acid oxidation NHL: non-Hodgkin lymphoma GLUT1: Glucose Transporter Type 1 CML: chronic myeloid leukemia CAFs: cancer-associated fibroblasts ECM: extracellular matrix PHD: prolyl hydroxylase domain NSCLC: non-small cell lung cancer STAT3: signal transducer and activator of transcription 3 HO-1: heme oxygenase-1 REDD1: regulated in development and DNA damage 1 DCs: dendritic cells cDC: conventional dendritic cell MHC: major histocompatibility complex pDC: plasmacytoid dendritic cell TLR: Toll-like receptor tDC: tumor-associated dendritic cell TIM3: T-cell immunoglobulin and mucin domain-containing protein 3 CTLs: cytotoxic T lymphocytes Th cells: helper T cells PGC-1: proliferator-activated receptor gamma coactivator 1-alpha NFAT: nuclear factor of activated T cell SENP3: SUMO-specific protease 3 BACH2: BTB domain and CNC homolog 2 IDO: indoleamine 2,3-dioxygenase GSK-3: glycogen synthase kinase-3 ADCC: antibody-dependent cell-mediated cytotoxicity IFN-: interferon-gamma Drp1: dynamic-related protein 1 CAMs: cancer-associated macrophages VEGF: vascular endothelial growth factor DAMPs: damage-associated molecular patterns PGE2: prostaglandin E2 MDSCs: myeloid-derived suppressor cells TANs: tumor-associated neutrophils ICIs: immune checkpoint inhibitors ICD: immunogenic cell death DOX: doxorubicin CRT: calreticulin CTLA-4: cytotoxic T-lymphocyte-associated protein 4 TNBC: triple-negative breast cancer TXN-1: thioredoxin-1 NAC: N-acetylcysteine NMN: nicotinamide mononucleotide TIGIT: T-cell immunoglobulin and ITIM domain CISH: cytokine-inducible SH2-containing protein PDT: photodynamic therapy RT: radiotherapy dsDNA: double-stranded DNA Holo-Lf: Holo-lactoferrin DSBs: double-strand breaks cGAS: cyclic GMP-AMP synthase STING: stimulator of interferon genes HCC: hepatocellular carcinoma GSTZ1: Glutathione S-Transferase Z1 -TOS: -tocopheryl succinate -T3: -tocotrienol TPP+: triphenylphosphonium NSAIDs: nonsteroidal anti-inflammatory drugs BAD: Bcl-2-associated death promoter NPs: nanoparticles DHODH: dihydroorotate dehydrogenase IRF1: interferon regulatory factor 1 SDT: sonodynamic therapy UCNPs: upconversion nanoparticles TPZ: tirapazamine EPR: enhanced permeability and retention scRNA-seq: single-cell RNA sequencing ST: spatial transcriptomics LUSC: lung squamous cell carcinoma ICB: immune checkpoint blockade AGMAT: agmatinase miRNAs: microRNAs AI: artificial intelligence ML: machine learning CTC: circulating tumor cell ATO: arsenic trioxide 2-ME: 2-Methoxyestradiol SOCE: store-operated Ca2 + entry 2-DG: 2-deoxy-D-glucose SIRTs: Sirtuins HRE: hypoxia-response element BCR: B-cell receptor CSCs: cancer stem cells References Mattiuzzi C, Lippi G

doi: 10.3389/fimmu.2025.1634516 39 LapaquettePTerratSProukhnitzkyLMartineLGrgoireSButeauBet al

doi: 10.1371/journal.pone.0058929 14 ChiyomaruT.YamamuraS.ZamanM

The -cyano amide-based Michael acceptors have also been elegantly used by the Taunton group as warheads in small-molecule inhibitors to react with active site cysteines while being minimally affected by the high concentration of intracellular GSH due to the fast reaction kinetics and the mM of K d (refs 31, 32)