Background: Throughout oral squamous cell carcinoma (OSCC) progression, tumor-associated macrophages (TAMs) lose their antigen-presenting capacity and anti-tumor function. The mechanisms that cause this dysfunction are not fully understood. CD74 is essential for antigen-presenting process, while little direct evidence describes its role in TAMs' immune function.
Methods: We integrated single-cell transcriptomic analysis, clinical cohort validation and CD74 conditional knockout mouse model to investigate the role of CD74 in TAMs during OSCC progression. Metabolomic analysis and mechanistic studies were performed to dissect how lactate-mediated metabolic reprogramming regulates CD74 expression.
Results: We demonstrate that lactate accumulation in TME induces metabolic reprogramming of TAMs, which drives the acetylation of C/EBPα, and consequently suppresses CD74 expression. This downregulation of CD74 impairs the antigen-presenting capacity of TAMs, suppresses T cell activation, and ultimately promotes OSCC progression and recurrence.
Conclusions: Our findings reveal the critical role of the lactate-C/EBPα-CD74 axis in shaping TAMs function, and provide potential therapeutic target for OSCC immunotherapy.
Key points:
| [1] |
Easwaran M, Madasamy S, Venkidasamy B. Theranostic potential of bacteriophages against oral squamous cell carcinoma. Curr Gene Ther. 2025; 25(2): 89-91.
|
| [2] |
Wu C, Zhou K, Zhao T, Zhao L, Wang H, Feng H. Tertiary lymphoid structures gene signature predicts prognosis and immune infiltration analysis in head and neck squamous cell carcinoma. Curr Genomics. 2024; 25(2): 88-104.
|
| [3] |
Zhang Y, Zhao Z, Huang W, et al. Pan-cancer single-cell analysis revealing the heterogeneity of cancer- associated fibroblasts in skin tumors. Curr Gene Ther. 2025; 25(5): 793-821.
|
| [4] |
Swanton C, Bernard E, Abbosh C, et al. Embracing cancer complexity: hallmarks of systemic disease. Cell. 2024; 187(7): 1589-1616.
|
| [5] |
Baqai N, Amin R, Fatima T, Ahmed Z, Faiz N. Expression profiling of EMT transcriptional regulators ZEB1 and ZEB2 in different histopathological grades of oral squamous cell carcinoma patients. Curr Genomics. 2024; 25(2): 140-151.
|
| [6] |
Li M, Yang Y, Xiong L, Jiang P, Wang J, Li C. Metabolism, metabolites, and macrophages in cancer. J Hematol Oncol. 2023; 16(1): 80.
|
| [7] |
Hu Y, He MY, Zhu LF, et al. Tumor-associated macrophages correlate with the clinicopathological features and poor outcomes via inducing epithelial to mesenchymal transition in oral squamous cell carcinoma. J Exp Clin Cancer Res. 2016; 35: 12.
|
| [8] |
Lee SY, Jhun J, Woo JS, et al. Gut microbiome-derived butyrate inhibits the immunosuppressive factors PD-L1 and IL-10 in tumor-associated macrophages in gastric cancer. Gut Microbes. 2024; 16(1):2300846.
|
| [9] |
Wei YT, Wang XR, Yan C, et al. Thymosin α-1 reverses M2 polarization of tumor-associated macrophages during efferocytosis. Cancer Res. 2022; 82(10): 1991-2002.
|
| [10] |
Waibl Polania J, Hoyt-Miggelbrink A, Tomaszewski WH, et al. Antigen presentation by tumor-associated macrophages drives T cells from a progenitor exhaustion state to terminal exhaustion. Immunity. 2025; 58(1): 232-246.e236.
|
| [11] |
Yang K, Halima A, Chan TA. Antigen presentation in cancer—mechanisms and clinical implications for immunotherapy. Nat Rev Clin Oncol. 2023; 20(9): 604-623.
|
| [12] |
Pishesha N, Harmand TJ, Ploegh HL. A guide to antigen processing and presentation. Nat Rev Immunol. 2022; 22(12): 751-764.
|
| [13] |
Kruse B, Buzzai AC, Shridhar N, et al. CD4(+) T cell-induced inflammatory cell death controls immune-evasive tumours. Nature. 2023; 618(7967): 1033-1040.
|
| [14] |
Kilian M, Sheinin R, Tan CL, et al. MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors. Cancer Cell. 2023; 41(2): 235-251.e239.
|
| [15] |
Alspach E, Lussier DM, Miceli AP, et al. MHC-II neoantigens shape tumour immunity and response to immunotherapy. Nature. 2019; 574(7780): 696-701.
|
| [16] |
Chang YC, Chen TC, Lee CT, et al. Epigenetic control of MHC class II expression in tumor-associated macrophages by decoy receptor 3. Blood. 2008; 111(10): 5054-5063.
|
| [17] |
Thibodeau J, Bourgeois-Daigneault MC, Lapointe R. Targeting the MHC class II antigen presentation pathway in cancer immunotherapy. Oncoimmunology. 2012; 1(6): 908-916.
|
| [18] |
Bonnin E, Rodrigo Riestra M, Marziali F, et al. CD74 supports accumulation and function of regulatory T cells in tumors. Nat Commun. 2024; 15(1): 3749.
|
| [19] |
Qiu Z, Khalife J, Ethiraj P, et al. IRF8-mutant B cell lymphoma evades immunity through a CD74-dependent deregulation of antigen processing and presentation in MHC II complexes. Sci Adv. 2024; 10(28):eadk2091.
|
| [20] |
Xiao N, Li K, Zhu X, et al. CD74(+) macrophages are associated with favorable prognosis and immune contexture in hepatocellular carcinoma. Cancer Immunol Immunother. 2022; 71(1): 57-69.
|
| [21] |
He W, Heinz A, Jahn D, Hiller K. Complexity of macrophage metabolism in infection. Curr Opin Biotechnol. 2021; 68: 231-239.
|
| [22] |
García-Cañaveras JC, Chen L, Rabinowitz JD. The tumor metabolic microenvironment: lessons from lactate. Cancer Res. 2019; 79(13): 3155-3162.
|
| [23] |
Colegio OR, Chu NQ, Szabo AL, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014; 513(7519): 559-563.
|
| [24] |
Zhang J, Muri J, Fitzgerald G, et al. Endothelial lactate controls muscle regeneration from ischemia by inducing M2-like macrophage polarization. Cell Metab. 2020; 31(6): 1136-1153.e1137.
|
| [25] |
Zhang D, Tang Z, Huang H, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019; 574(7779): 575-580.
|
| [26] |
De Leo A, Ugolini A, Yu X, et al. Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma. Immunity. 2024; 57(5): 1105-1123.e1108.
|
| [27] |
Wang J, Yang P, Yu T, et al. Lactylation of PKM2 suppresses inflammatory metabolic adaptation in pro-inflammatory macrophages. Int J Biol Sci. 2022; 18(16): 6210-6225.
|
| [28] |
Shi W, Cassmann TJ, Bhagwate AV, Hitosugi T, Ip WKE. Lactic acid induces transcriptional repression of macrophage inflammatory response via histone acetylation. Cell Rep. 2024; 43(2):113746.
|
| [29] |
Zhang X, Yue L, Cao L, et al. Tumor microenvironment-responsive macrophage-mediated immunotherapeutic drug delivery. Acta Biomater. 2024; 186: 369-382.
|
| [30] |
Ji S, Shi Y, Yin B. Macrophage barrier in the tumor microenvironment and potential clinical applications. Cell Commun Signal. 2024; 22(1): 74.
|
| [31] |
Pitter MR, Kryczek I, Zhang H, et al. PAD4 controls tumor immunity via restraining the MHC class II machinery in macrophages. Cell Rep. 2024; 43(3):113942.
|
| [32] |
Li Y, Shen Z, Chai Z, et al. Targeting MS4A4A on tumour-associated macrophages restores CD8+ T-cell-mediated antitumour immunity. Gut. 2023; 72(12): 2307-2320.
|
| [33] |
Mensali N, Grenov A, Pati NB, et al. Antigen-delivery through invariant chain (CD74) boosts CD8 and CD4 T cell immunity. Oncoimmunology. 2019; 8(3):1558663.
|
| [34] |
Schröder B, Saftig P. Intramembrane proteolysis within lysosomes. Ageing Res Rev. 2016; 32: 51-64.
|
| [35] |
Su H, Na N, Zhang X, Zhao Y. The biological function and significance of CD74 in immune diseases. Inflamm Res. 2017; 66(3): 209-216.
|
| [36] |
Cheng J, Li J, Jiang X, et al. CD74 facilitates immunotherapy response by shaping the tumor microenvironment of hepatocellular carcinoma. Mol Med. 2024; 30(1): 116.
|
| [37] |
Valiño-Rivas L, Baeza-Bermejillo C, Gonzalez-Lafuente L, Sanz AB, Ortiz A, Sanchez-Niño MD. CD74 in kidney disease. Front Immunol. 2015; 6: 483.
|
| [38] |
Balakrishnan CK, Tye GJ, Balasubramaniam SD, Kaur G. CD74 and HLA-DRA in cervical carcinogenesis: potential targets for antitumour therapy. Medicina (Kaunas). 2022; 58(2): 190.
|
| [39] |
Wang Z, Wang B, Feng Y, et al. Targeting tumor-associated macrophage-derived CD74 improves efficacy of neoadjuvant chemotherapy in combination with PD-1 blockade for cervical cancer. J Immunother Cancer. 2024; 12(8):e009024.
|
| [40] |
Wang D, Li S, Yang Z, et al. Single-cell transcriptome analysis deciphers the CD74-mediated immune evasion and tumour growth in lung squamous cell carcinoma with chronic obstructive pulmonary disease. Clin Transl Med. 2024; 14(8):e1786.
|
| [41] |
Chen D, Zhang X, Li Z, Zhu B. Metabolic regulatory crosstalk between tumor microenvironment and tumor-associated macrophages. Theranostics. 2021; 11(3): 1016-1030.
|
| [42] |
Zhang CJ, Li JM, Xu D, et al. Surface molecularly engineered mitochondria conduct immunophenotype repolarization of tumor-associated macrophages to potentiate cancer immunotherapy. Adv Sci (Weinh). 2024; 11(38):e2403044.
|
| [43] |
Weng SW, Wu JC, Shen FC, et al. Chaperonin counteracts diet-induced non-alcoholic fatty liver disease by aiding sirtuin 3 in the control of fatty acid oxidation. Diabetologia. 2023; 66(5): 913-930.
|
| [44] |
Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017; 14(7): 399-416.
|
| [45] |
Li W, Zhou C, Yu L, et al. Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer. Autophagy. 2024; 20(1): 114-130.
|
| [46] |
Faubert B, Li KY, Cai L, et al. Lactate metabolism in human lung tumors. Cell. 2017; 171(2): 358-371.e359.
|
| [47] |
Cai X, Ng CP, Jones O, et al. Lactate activates the mitochondrial electron transport chain independently of its metabolism. Mol Cell. 2023; 83(21): 3904-3920.e3907.
|
| [48] |
Sun Z, Ji Z, Meng H, et al. Lactate facilitated mitochondrial fission-derived ROS to promote pulmonary fibrosis via ERK/DRP-1 signaling. J Transl Med. 2024; 22(1): 479.
|
| [49] |
Ligeon LA, Pena-Francesch M, Vanoaica LD, et al. Oxidation inhibits autophagy protein deconjugation from phagosomes to sustain MHC class II restricted antigen presentation. Nat Commun. 2021; 12(1): 1508.
|
| [50] |
Ye L, Jiang Y, Zhang M. Crosstalk between glucose metabolism, lactate production and immune response modulation. Cytokine Growth Factor Rev. 2022; 68: 81-92.
|
| [51] |
Huang Y, Luo G, Peng K, et al. Lactylation stabilizes TFEB to elevate autophagy and lysosomal activity. J Cell Biol. 2024;223(11):e202308099.
|
| [52] |
Beswick EJ, Reyes VE. CD74 in antigen presentation, inflammation, and cancers of the gastrointestinal tract. World J Gastroenterol. 2009; 15(23): 2855-2861.
|
| [53] |
Wang D, Sun T, Xia Y, et al. Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation. Nat Commun. 2023; 14(1): 6907.
|
| [54] |
Twu YC, Hsieh CY, Lin M, Tzeng CH, Sun CF, Yu LC. Phosphorylation status of transcription factor C/EBPalpha determines cell-surface poly-LacNAc branching (I antigen) formation in erythropoiesis and granulopoiesis. Blood. 2010; 115(12): 2491-2499.
|
| [55] |
Radomska HS, Bassères DS, Zheng R, et al. Block of C/EBP alpha function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations. J Exp Med. 2006; 203(2): 371-381.
|
| [56] |
Bararia D, Kwok HS, Welner RS, et al. Acetylation of C/EBPα inhibits its granulopoietic function. Nat Commun. 2016; 7(1):10968.
|
| [57] |
Mozzetta C, Sartorelli V, Steinkuhler C, Puri PL. HDAC inhibitors as pharmacological treatment for Duchenne muscular dystrophy: a discovery journey from bench to patients. Trends Mol Med. 2024; 30(3): 278-294.
|
RIGHTS & PERMISSIONS
2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
PDF
(16269KB)
