Weighing Translocons Sec Roles in Breast Cancer Cross Presentation Major Translocons
Abstract
Background: Translocons Sec61, Sec62, and Sec22B occupy a central yet underappreciated position in the regulation of antigen cross-presentation. Rather than serving redundant roles, each contributes a distinct function within ER-associated antigen processing. Sec61 primarily facilitates the translocation of internalized antigens into the cytosol for proteasomal processing, whereas Sec62 enables the selective re-entry of processed peptides into the endoplasmic reticulum through mechanisms that can bypass canonical TAP dependency. In parallel, Sec22B governs ER–phagosome fusion and vesicular trafficking, thereby shaping the spatial and temporal organization required for efficient peptide loading and MHC-class I transport. In this Review, we synthesize emerging evidence to argue that Sec translocons represent overlooked determinants in antigen presentation and may hold therapeutic relevance in breast cancer.
Methods: Parallel inquiries in the PubMed database were performed with a query of Sec breast cancer. Subsequent assessments were manually conducted according to the relevance of the papers to our area of interest.
Results: A total of 554 publications containing either of the query sets were identified. Following further assessment, 72publications were included. . The original research articles are scarce with majority were in vitro studies.
Conclusion: Sec61, Sec62, and Sec22B form a regulatory axis in bidirectional tumor-peptide trafficking across ER-associated compartments that governs antigen cross-presentation. By shaping antigen availability and immune recognition, these translocons may critically influence tumor behavior and represent promising targets for improving immunotherapeutic strategies in breast cancer.
Full text article
References
Khan MM, Yalamarty SSK, Rajmalani BA, Filipczak N, Torchilin VP. Recent strategies to overcome breast cancer resistance. Crit Rev Oncol Hematol. 2024;197: 104351. doi:10.1016/j.critrevonc.2024.104351
Prihantono, Faruk M. Breast cancer resistance to chemotherapy: When should we suspect it and how can we prevent it? Ann Med Surg. 2021;70: 102793. doi:10.1016/j.amsu.2021.102793
Rivas EI, Linares J, Zwick M, Gómez-Llonin A, Guiu M, Labernadie A, et al. Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors. Nat Commun. 2022;13: 5310. doi:10.1038/s41467-022-32782-3
Morillo-Huesca M, G López-Cepero I, Conesa-Bakkali R, Tomé M, Watts C, Huertas P, et al. Radiotherapy resistance driven by Asparagine endopeptidase through ATR pathway modulation in breast cancer. J Exp Clin Cancer Res. 2025;44: 74. doi:10.1186/s13046-025-03334-6
Yu S, Wang C, Ouyang J, Luo T, Zeng F, Zhang Y, et al. Identification of candidate biomarkers correlated with the pathogenesis of breast cancer patients. Sci Rep. 2025;15: 8770. doi:10.1038/s41598-025-93208-w
Nurlaila I. Deciphering Antigen Processing Machinery (APM) as One of the Determinants for Responsiveness of Affected Patients towards Anticancer Immunotherapy. Asian Pacific J cancer Prev. 2024;25: 4457–4464. doi:10.31557/APJCP.2024.25.12.4457
Thompson JC, Davis C, Deshpande C, Hwang W-T, Jeffries S, Huang A, et al. Gene signature of antigen processing and presentation machinery predicts response to checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma. J Immunother Cancer. 2020;8: e000974. doi:10.1136/jitc-2020-000974
Pfeffer S, Dudek J, Schaffer M, Ng BG, Albert S, Plitzko JM, et al. Dissecting the molecular organization of the translocon-associated protein complex. Nat Commun. 2017;8: 14516. doi:10.1038/ncomms14516
Zehner M, Marschall AL, Bos E, Schloetel J-G, Kreer C, Fehrenschild D, et al. The Translocon Protein Sec61 Mediates Antigen Transport from Endosomes in the Cytosol for Cross Presentation to CD8 T Cells. Immunity. 2015;42: 850–863. doi:10.1016/j.immuni.2015.04.008
Lau D, Elliott T. Imaging antigen processing and presentation in cancer. Immunother Adv. 2025;5: ltaf002. doi:10.1093/immadv/ltaf002
Domenger A, Choisy C, Baron L, Mayau V, Perthame E, Deriano L, et al. The Sec61 translocon is a therapeutic vulnerability in multiple myeloma. EMBO Mol Med. 2022;14. doi:10.15252/emmm.202114740
Deshaies RJ, Schekman R. A yeast mutant defective at an early stage in import of secretory protein precursors into the endoplasmic reticulum. J Cell Biol. 1987;105: 633–645. doi:10.1083/jcb.105.2.633
Robinson DR, Kalyana-Sundaram S, Wu Y-M, Shankar S, Cao X, Ateeq B, et al. Functionally Recurrent Rearrangements of the MAST Kinase and Notch Gene Families in Breast Cancer. Nat Med. 2012;17: 1646–1651. doi:10.1038/nm.2580
Ma J, He Z, Zhang H, zhang W, Gao S, Ni X. SEC61G promotes breast cancer development and metastasis via modulating glycolysis and is transcriptionally regulated by E2F1. Cell Death Dis. 2021;12: 550. doi:10.1038/s41419-021-03797-3
Jin L, Chen D, Hirachan S, Bhandari A, Huang Q. SEC61G regulates breast cancer cell proliferation and metastasis by affecting the Epithelial-Mesenchymal Transition. J Cancer. 2022;13: 831–846. doi:10.7150/jca.65879
Ruiz-saenz A, Sandhu M, Carrasco Y, Maglathlin RL, Moasser MM. Targeting HER3 by interfering with its Sec61-mediated cotranslational insertion into the endoplasmic reticulum. Oncogene. 2015;34: 5288–5294. doi:10.1038/onc.2014.455.
Radosa JC, Kasoha M, Doerk M, Cullmann A, Kaya AC, Linxweiler M, et al. The 3q Oncogene SEC62 Predicts Response to Neoadjuvant Chemotherapy and Regulates Tumor Cell Migration in Triple Negative Breast Cancer. Int J Mol Sci. 2023;24. doi:10.3390/ijms24119576
Takacs FZ, Radosa JC, Linxweiler M, Kasoha M, Bohle RM, Bochen F, et al. Identification of 3q oncogene SEC62 as a marker for distant metastasis and poor clinical outcome in invasive ductal breast cancer. Arch Gynecol Obstet. 2019;299: 1405–1413. doi:10.1007/s00404-019-05081-4
Baleeiro RB, Rietscher R, Diedrich A, Czaplewska JA, Lehr CM, Scherließ R, et al. Spatial separation of the processing and MHC class I loading compartments for cross-presentation of the tumor-associated antigen HER2/neu by human dendritic cells. Oncoimmunology. 2015;4. doi:10.1080/2162402X.2015.1047585
Cruz FM, Chan A, Rock KL. Pathways of MHC I cross-presentation of exogenous antigens. Semin Immunol. 2023;66: 101729. doi:10.1016/j.smim.2023.101729
Colbert JD, Cruz FM, Rock KL. Cross-presentation of exogenous antigens on MHC I molecules. Curr Opin Immunol. 2020;64: 1–8. doi:10.1016/j.coi.2019.12.005
Shen H, Xu D, Chen W. Integration of bioinformatics and machine learning strategies identifies APM-related gene signatures to predict clinical outcomes and therapeutic responses for breast cancer patients. Neoplasia. 2023;13. doi:10.1016/j.neo.2023.100942
Murtadha AH, Sharudin NA, Azahar IIM, Che Has AT, Mokhtar NF. Upregulation of MHC I Antigen Processing Machinery Gene Expression in Breast Cancer Cells by Trichostatin A. Mol Biol. 2024;58: 121–125. doi:10.1134/S0026893324010151
Lee MY, Jeon JW, Sievers C, Allen CT. Antigen processing and presentation in cancer immunotherapy. J Immunother cancer. 2020;8. doi:10.1136/jitc-2020-001111
Chang Q, Zhang Y, Liu X, Miao P, Pu W, Liu S, et al. Oxidative Stress in Antigen Processing and Presentation. MedComm – Oncol. 2025;4: e70020. doi:10.1002/mog2.70020
Morisaki T, Kubo M, Umebayashi M, Yew PY, Yoshimura S, Park J-H, et al. Neoantigens elicit T cell responses in breast cancer. Sci Rep. 2021;11: 13590. doi:10.1038/s41598-021-91358-1
Blander JM. Regulation of the Cell Biology of Antigen Cross-Presentation. Annu Rev Immunol. 2018;36: 717–753. doi:10.1146/annurev-immunol-041015-055523
Mediani L, Guillén-Boixet J, Vinet J, Franzmann TM, Bigi I, Mateju D, et al. Defective ribosomal products challenge nuclear function by impairing nuclear condensate dynamics and immobilizing ubiquitin. EMBO J. 2019;38: e101341. doi:10.15252/embj.2018101341
Cruz FM, Orellano LAA, Chan A, Rock KL. Alternate MHC I Antigen Presentation Pathways Allow CD8+ T-cell Recognition and Killing of Cancer Cells in the Absence of β2M or TAP. Cancer Immunol Res. 2025;13: 98–108. doi:10.1158/2326-6066.CIR-24-0320
Giodini A, Cresswell P. Hsp90‐mediated cytosolic refolding of exogenous proteins internalized by dendritic cells. EMBO J. 2008;27: 201–211. doi:10.1038/sj.emboj.7601941
Springer S. Transport and quality control of MHC class I molecules in the early secretory pathway. Curr Opin Immunol. 2015;34: 83–90. doi:10.1016/j.coi.2015.02.009
Merzougui N, Kratzer R, Saveanu L, van Endert P. A proteasome‐dependent, TAP‐independent pathway for cross‐presentation of phagocytosed antigen. EMBO Rep. 2011;12: 1257–1264. doi:10.1038/embor.2011.203
Campbell DJ, Serwold T, Shastri N. Bacterial Proteins Can Be Processed by Macrophages in a Transporter Associated with Antigen Processing-Independent, Cysteine Protease-Dependent Manner for Presentation by MHC Class I Molecules1. J Immunol. 2000;164: 168–175. doi:10.4049/jimmunol.164.1.168
Asea A, Rehli M, Kabingu E, Boch JA, Baré O, Auron PE, et al. Novel Signal Transduction Pathway Utilized by Extracellular HSP70. J Biol Chem. 2002;277: 15028–15034. doi:10.1074/jbc.M200497200
Li B, Hu L. Cross-presentation of Exogenous Antigens. Transfus Clin Biol. 2019;26: 346–351. doi:10.1016/j.tracli.2019.01.006
Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480: 480–489. doi:10.1038/nature10673
Meier M, Scholz SA, von Bank L, Levandoski JE, Lückhof M, Schaaf M, et al. Functional Mapping and Engineering of the Sec Translocon Unlocked by a Cell-Free System. bioRxiv. 2025; 2025.12.09.688994. doi:10.64898/2025.12.09.688994
Vitale M, Rezzani R, Rodella L, Zauli G, Grigolato P, Cadei M, et al. HLA class I antigen and transporter associated with antigen processing (TAP1 and TAP2) down-regulation in high-grade primary breast carcinoma lesions. Cancer Res. 1998;58: 737–742.
Song D, Liu H, Wu J, Gao X, Hao J, Fan D. Insights into the role of ERp57 in cancer. J Cancer. 2021;12: 2456–2464. doi:10.7150/jca.48707
Chen H, Li L, Weimershaus M, Evnouchidou I, van Endert P, Bouvier M. ERAP1-ERAP2 dimers trim MHC I-bound precursor peptides; implications for understanding peptide editing. Sci Rep. 2016;6: 28902. doi:10.1038/srep28902
Henle AM, Nassar A, Puglisi-Knutson D, Youssef B, Knutson KL. Downregulation of TAP1 and TAP2 in early stage breast cancer. PLoS One. 2017;12: e0187323. doi:10.1371/journal.pone.0187323
Alloatti A, Rookhuizen DC, Joannas L, Carpier J-M, Iborra S, Magalhaes JG, et al. Critical role for Sec22b-dependent antigen cross-presentation in antitumor immunity. J Exp Med. 2018;214: 1001. doi:10.1084/jem.2017022902092018c
Linxweiler M, Schick B, Zimmermann R. Let’s talk about Secs: Sec61, Sec62 and Sec63 in signal transduction, oncology and personalized medicine. Signal Transduct Target Ther. 2017;2: 17002. doi:10.1038/sigtrans.2017.2
Parys JB, Van Coppenolle F. Sec61 complex/translocon: The role of an atypical ER Ca(2+)-leak channel in health and disease. Front Physiol. 2022;13: 991149. doi:10.3389/fphys.2022.991149
Grotzke JE, Kozik P, Morel J-D, Impens F, Pietrosemoli N, Cresswell P, et al. Sec61 blockade by mycolactone inhibits antigen cross-presentation independently of endosome-to-cytosol export. Immunol Inflamm. 2017;114: E5910–E5919. doi:10.1073/pnas.1705242114
Schäuble N, Lang S, Jung M, Cappel S, Schorr S, Ulucan Ö, et al. BiP-mediated closing of the Sec61 channel limits Ca2+ leakage from the ER. EMBO J. 2012;31: 3282–3296. doi:10.1038/emboj.2012.189
Pick T, Beck A, Gamayun I, Schwarz Y, Schirra C, Jung M, et al. Remodelling of Ca2+ homeostasis is linked to enlarged endoplasmic reticulum in secretory cells. Cell Calcium. 2021;99: 102473. doi:10.1016/j.ceca.2021.102473
Harsman A, Kopp A, Wagner R, Zimmermann R, Jung M. Calmodulin regulation of the calcium-leak channel Sec61 is unique to vertebrates. Channels (Austin). 2011;5: 293–298. doi:10.4161/chan.5.4.16160
Lakkaraju AKK, Thankappan R, Mary C, Garrison JL, Taunton J, Strub K. Efficient secretion of small proteins in mammalian cells relies on Sec62-dependent posttranslational translocation. Mol Biol Cell. 2012;23: 2712–2722. doi:10.1091/mbc.E12-03-0228
Jung V, Kindich R, Kamradt J, Jung M, Müller M, Schulz WA, et al. Genomic and expression analysis of the 3q25-q26 amplification unit reveals TLOC1/SEC62 as a probable target gene in prostate cancer. Mol Cancer Res. 2006;4: 169–176. doi:10.1158/1541-7786.MCR-05-0165
Hagerstrand D, Tong A, Schumacher SE, Ilic N, Shen RR, Cheung HW, et al. Systematic Interrogation of 3q26 Identifies TLOC1 and SKIL as Cancer Drivers. Cancer Discov. 2013;3: 1044–1057. doi:10.1158/2159-8290.CD-12-0592
Bergmann TJ, Fumagalli F, Loi M, Molinari M. Role of SEC62 in ER maintenance: A link with ER stress tolerance in SEC62-overexpressing tumors? Mol Cell Oncol. 2017;4: e1264351. doi:10.1080/23723556.2016.1264351
Zimmermann JSM, Linxweiler J, Radosa JC, Linxweiler M, Zimmermann R. The endoplasmic reticulum membrane protein Sec62 as potential therapeutic target in SEC62 overexpressing tumors. Front Physiol. 2022;Volume 13. doi:10.3389/fphys.2022.1014271
Körner S, Pick T, Bochen F, Wemmert S, Körbel C, Menger MD, et al. Antagonizing Sec62 function in intracellular Ca2+ homeostasis represents a novel therapeutic strategy for head and neck cancer. Front Physiol. 2022;13: 880004. doi:10.3389/fphys.2022.880004
Biscari L, Maza MC, Farré C, Kaufman CD, Amigorena S, Fresno M, et al. Sec22b-dependent antigen cross-presentation is a significant contributor of T cell priming during infection with the parasite Trypanosoma cruzi. Front Cell Dev Biol. 2023;11: 1–9. doi:10.3389/fcell.2023.1138571
Wu SJ, Niknafs YS, Kim SH, Oravecz-Wilson K, Zajac C, Toubai T, et al. A Critical Analysis of the Role of SNARE Protein SEC22B in Antigen Cross-Presentation. Cell Rep. 2017;19: 2645–2656. doi:10.1016/j.celrep.2017.06.013
Meng J, Wang J. Role of SNARE proteins in tumourigenesis and their potential as targets for novel anti-cancer therapeutics. Biochim Biophys Acta. 2015;1856: 1–12. doi:10.1016/j.bbcan.2015.04.002
Liu H, Dang R, Zhang W, Hong J, Li X. SNARE proteins: Core engines of membrane fusion in cancer. Biochim Biophys Acta - Rev Cancer. 2024; 189148. doi:10.1016/j.bbcan.2024.189148
Duque GA, Dion R, Fabie A, Descoteaux J, Stager S, Descoteaux A, et al. Sec22b regulates inflammatory responses by controlling the nuclear translocation of NF-κB. J Immunol. 2020;207: 2297–2309. doi:10.4049/jimmunol.2100258
Alloatti A, Rookhuizen DC, Joannas L, Carpier J-M, Iborra S, Magalhaes JG, et al. Critical role for Sec22b-dependent antigen cross-presentation in antitumor immunity. J Exp Med. 2017;214: 2231–2241. doi:10.1084/jem.20170229
Cebrian I, Visentin G, Blanchard N, Jouve M, Bobard A, Moita C, et al. Sec22b regulates phagosomal maturation and antigen crosspresentation by dendritic cells. Cell. 2011;147: 1355–1368. doi:10.1016/j.cell.2011.11.021
Yewdell JW, Snyder HL, Bacik I, Antón LC, Deng Y, Behrens TW, et al. TAP-independent delivery of antigenic peptides to the endoplasmic reticulum: therapeutic potential and insights into TAP-dependent antigen processing. J Immunother. 1998;21: 127–131. doi:10.1097/00002371-199803000-00006
Sun W, Tian B-X, Wang S-H, Liu P-J, Wang Y-C. The function of SEC22B and its role in human diseases. Cytoskeleton. 2020;77: 303–312. doi:10.1002/cm.21628
Almanza A, Carlesso A, Chintha C, Creedican S, Doultsinos D, Leuzzi B, et al. Endoplasmic reticulum stress signalling - from basic mechanisms to clinical applications. FEBS J. 2019;286: 241–278. doi:10.1111/febs.14608
Witham CM, Paxman AL, Baklous L, Steuart RFL, Schulz BL, Mousley CJ. Cancer associated mutations in Sec61γ alter the permeability of the ER translocase. PLoS Genet. 2021;17: 1–19. doi:10.1371/journal.pgen.1009780
Kang S-W, Rane NS, Kim SJ, Garrison JL, Taunton J, Hegde RS. Substrate-Specific Translocational Attenuation during ER Stress Defines a Pre-Emptive Quality Control Pathway. Cell. 2006;127: 999–1013. doi:https://doi.org/10.1016/j.cell.2006.10.032
Morel J-D, Paatero AO, Wei J, Yewdell JW, Guenin-Macé L, Van Haver D, et al. Proteomics Reveals Scope of Mycolactone-mediated Sec61 Blockade and Distinctive Stress Signature*. Mol Cell Proteomics. 2018;17: 1750–1765. doi:https://doi.org/10.1074/mcp.RA118.000824
Gu J, He Y, He C, Zhang Q, Huang Q, Bai S, et al. Advances in the structures, mechanisms and targeting of molecular chaperones. Signal Transduct Target Ther. 2025;10: 84. doi:10.1038/s41392-025-02166-2
Haßdenteufel S, Nguyen D, Helms V, Lang S, Zimmermann R. ER import of small human presecretory proteins: components and mechanisms. FEBS Lett. 2019;593: 2506–2524. doi:https://doi.org/10.1002/1873-3468.13542
Steinberg R, Origi A, Natriashvili A, Sarmah P, Licheva M, Walker PM, et al. Posttranslational insertion of small membrane proteins by the bacterial signal recognition particle. PLoS Biol. 2020;18: e3000874. doi:10.1371/journal.pbio.3000874
Adnan M, Islam W, Zhang J, Zheng W, Lu G-D. Diverse Role of SNARE Protein Sec22 in Vesicle Trafficking, Membrane Fusion, and Autophagy. Cells. 2019;8. doi:10.3390/cells8040337
Schnell DJ, Hebert DN. Protein Translocons: Multifunctional Mediators of Protein Translocation across Membranes. Cell. 2003;112: 491–505. doi:10.1016/S0092-8674(03)00110-7
Authors
Copyright (c) 2026 Archives of Breast Cancer
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Copyright©. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International License, which permits copy and redistribution of the material in any medium or format or adapt, remix, transform, and build upon the material for any purpose, except for commercial purposes.