Cross-presentation, the process by which dendritic cells (DCs) present exogenous antigens on major histocompatibility complex (MHC)-class I molecules to activate CD8+ T cells, plays a crucial role in cancer immunity.20,21 This mechanism is governed by a set of genes referred to as APM.6,7,22,23

Figure 2 illustrates the 2 pathways of antigen presentation—classical MHC-class I processing and cross-presentation of exogenous antigens, which intersect in the display of processed peptides to CD8⁺ T lymphocytes. In the canonical MHC-class I pathway, endogenous antigens are loaded onto MHC-class I molecules prior to activation of effector mechanism by CD8+ T lymphocytes.24 These antigens encompass a broad spectrum, including misfolded or damaged proteins generated under cellular stress conditions, viral proteins synthesized during infections25, as well as tumor-associated antigens derived from mutated or abnormal cellular proteins, including neoantigens.26

Cellular stress responses further induce the formation of defective ribosomal products (DRiPs) which are subsequently degraded by proteasome into smaller peptide prior to their loading onto MHC-molecules.28 These peptide-MHC-class I complexes facilitate recognition by CD8+ T cells, thereby activating cytotoxic effector mechanisms aimed at eliminating cancer cells.29 Tumor antigens are processed via cytosolic or vacuolar pathways, distinguished by their reliance on proteasomal degradation and TAP-mediated transport. In the cytosolic route, substrates are either cleaved into immunogenic peptides or transiently stabilized by Hsp90, thereby regulating their availability for MHC class I presentation.30 Recent findings indicate that MHC-class I molecules are likely derived from secretory pathways.31,32 Within the vacuolar pathway, internalized antigens are processed by lysosomal proteases inside endocytic compartments and loaded onto recycling MHC class I molecules that return to the plasma membrane via early endosomes.33 Antigen properties shape pathway usage, as soluble or low-molecular-weight antigens preferentially access cytosolic processing, whereas particulate or Hsp-associated tumor antigens follow more heterogeneous presentation routes.34

Cross-presentation is also dictated by antigen-presenting cell identity: CD8-like DCs favor cytosolic processing, inflammatory DCs access both cytosolic and vacuolar routes, while B cells and bone marrow-derived DCs may rely on autophagy for antigens.35 Effective cancer immunotherapy depends on efficient cross-presentation.36 These processes implicate tightly-regulated antigen-processing networks by APM, including the underappreciated Sec translocon system.37

Despite their central role in protein trafficking, Sec translocons, such as Sec61, Sec62, and Sec22B have been relatively underrepresented in cancer immunology research compared with classical antigen processing components like, MHC, TAP, or the proteasomes.9 Accumulating evidence suggests that the translocons Sec61, Sec62, and Sec22B contribute to antigen processing and cross-presentation through complementary trafficking and translocation functions.9,13,17,18 However, their direct mechanistic integration has never been demonstrated, particularly in the context of BC. This absence of integrated analyses leaves unresolved the fundamental question of whether these translocons operate concurrently to sustain efficient cross-presentation, or whether their contributions are context- or compartment-specific. Addressing this question has been challenging, as no existing study has examined these components within a single experimental framework. Nevertheless, given that other elements of APM function as interdependent modules8,20,23,29,43,47,48,51, it is reasonable to hypothesize that disruption of any one of these Sec components may compromise the downstream immune outcomes. Because available studies have examined Sec61, Sec62, and Sec22B largely in distinct experimental frameworks, it remains unresolved whether these translocons act in a coordinated manner during antigen processing. Drawing on convergent evidence from independent lines of research, we propose that these Sec proteins constitute a spatially and temporally compartmentalized trafficking system, in which each component contributes a nonredundant yet complementary function to antigen translocation and cross-presentation rather than operating as a singular linear pathway.9,54,55 This conceptual integration provides a framework to reconcile prior discrepancies and highlights a previously underappreciated layer of regulation with potential relevance for antitumor immune competence.56 Below, we examine the Sec proteins that underpin this proposed antigen translocation framework.

Sec61 complex, which consists of 3 subunits (Sec61α, Sec61β, and Sec61γ), plays a key role in facilitating antigen transfer between endosomes and the cytosol.19 This complex has the ability to influence the expression of MHC-class I molecules in tumor cells, thereby affecting their immunogenic visibility.57 Sec61γ enhances the phosphorylation of the epidermal growth factor receptor (EGFR), which then activates downstream signaling pathways such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-Akt. This signals the synthesis of cell cycle regulators, which subsequently inhibit the phosphorylation of cyclin-dependent kinase 2 (CDK2). This inhibition facilitates the G1/S phase in the intracellular Ca2+ gradient mediated by calmodulin and dependent on its concentration.56,58,59

Most Ca2+ efflux is facilitated by the Sec61 heterotrimeric complex, which also mediates the translocation of newly-formed polypeptide chains into the lumen of the ER.46 The main physiological regulators of Ca²⁺ flux through Sec61 are the cytosolic Ca²⁺-calmodulin (CaM) complex and the luminal Hsp70-type chaperone-binding immunoglobulin protein (BiP), which interact directly with the Sec61α pore-forming subunit around tyrosine 344 to limit ER Ca2+.59,60 Another role of BiP is the regulation of Sec61-mediated Ca2+ leakage during cellular processes such as the unfolded protein response and apoptosis. Although the exact correlation between Sec61 and Ca2+ has not been definitively established, existing reports suggest that in the oncology framework of cancer, alterations in Sec61 and Ca2+ may represent a viable approach for anticancer treatment.56,58,59

To explain the regulatory mechanism of Sec61G in BC, Ma and colleagues (2021) performed bioinformatic analysis using the JASPAR database and Matrix Profile tool. They identified two transcription enhancement domain-associated (TEAD) binding elements (TBEs) suspected to be located within approximately 1 kb of the Sec61G promoter region. By engineering luciferase reporter constructs, containing wild-type or mutated E2F1 binding sequences, which were transfected together with control vectors or E2F1 overexpression vectors into HEK293 cells, they showed that E2F1 overexpression significantly increased luciferase activity, while TBE mutations reduced this effect. Moreover, using RNA immunoprecipitation (RIP) assays, they demonstrated that the downregulation of E2F1 significantly diminished the mRNA and protein levels of Sec61G in MCF-7 and MDA-MB-231 cell lines. Conversely, the upregulation of E2F1 corresponded with increased Sec61G expression. This finding suggests that E2F1 directly binds TBE region within the promoter of Sec61G, thereby influencing its transcriptional regulation.14

Reduction of Sec61G expression via shRNA significantly disrupted cisplatin-induced calcium release from the ER and decreased activation (phosphorylation) of the ERK1/2 and AMPK pathways. The acquisition of cancer stem cell (CSC) characteristics—such as increased expression of CSC markers, spheroid and colony formation, and invasive behavior—induced by cisplatin— can be effectively suppressed through Sec61G suppression and treatment with chloroquine, an autophagy inhibitor.15

Downregulation of Sec61 expression results in reduced cross-presentation of soluble ovalbumin (OVA) in the IFN-β-inducing adaptor (TRIF)-dependent signaling pathway containing the toll-like receptor/interleukin-1 (TIR) domain.9 When Sec61 release from the ER to endosomes is blocked using antibodies that fuse with the ER retention signal, there is a disruption in cross-presentation and antigen export to the cytosol. Experimental blocking or downregulation of Sec61 disrupts endosomal antigen export to the cytosol in DCs, reducing cross-presentation to CD8+ T cells, and tumor-associated regulators can exploit Sec61-related pathways to suppress MHC class I assembly and presentation.57

Sec62 represents another translocon component functionally aligned with Sec61, sharing its posttranslational protein translocation pathway while exerting distinct biological effects.61 Located at chromosome 3q26, Sec62 is frequently amplified in BC, where its overexpression correlates with invasive behavior and unfavorable prognosis.17,18 Mechanistically, Sec62-driven cellular transformation depends on its interaction with the RNA helicase DDX3X, a process mediated by the amino-terminal region of Sec62—a domain also implicated in ribosome association. DDX3X independently constitutes a component of poly-A-binding protein (PABP), which has been identified as a binding partner of Sec62. Consequently, the interaction between Sec62 and DDX3X influences a specific subset of mRNAs.62,63

Beyond its key role in ER protein translocation, Sec62 has emerged as a central regulator of recovER-phagy. It integrates protein import with ER quality control mechanisms that are increasingly recognized as critical determinants of tumor cell adaptation and survival.65

Due to its intracellular localization, the Sec62 protein exhibits limited accessibility to therapeutic antibodies.64 Therefore, effective Sec62 inactivation strategies emerge as the most viable strategy for prospective antineoplastic targeted therapy. By facilitating Ca2+ efflux from the ER lumen and consequently increasing cellular stress levels, functional blockade of Sec62 exhibits antiproliferative and anti-metastatic properties.64,66

In addition to Sec61 and Sec62, Sec22B also plays a major role in cross-presentation. This protein is a member of the soluble N-ethylmaleimide-sensitive receptor-associated proteins (SNARE) that facilitate vesicle fusion with membrane-bound organelles, including lysosomes.67,68 SNARE proteins are primarily involved in autophagy, which includes autophagosome formation, maturation, fusion with lysosomes, and subsequent degradation, all of which require effective membrane fusion. A growing body of evidence suggests that SNARE plays a key role in tumor development and progression, making it a promising target for new cancer therapies.69,70 In contrast to Sec61 and Sec62 translocons that operate largely in a unidirectional ER-to-Golgi manner, SNARE proteins exhibit dynamic cycling between ER and the Golgi apparatus. Their selective incorporation into coat protein complex II (COPII) vesicles departing the ER and COPI carriers which mediate retrograde Golgi transport is not incidental, but rather central to preserving the compositional and functional asymmetry of the early secretory pathway, a prerequisite for directional protein trafficking and membrane identity maintenance.71 Wu et al.72 generated a mouse model with targeted Sec22B deletion in DCs using CD11c-Cre Sec22Bfl/fl mice. They found that Sec22B deficiency did not impair the ability of DCs to cross-present these antigens. Both splenic CD11c+ Sec22B−/− DCs and bone marrow-derived DC lacking Sec22B exhibited normal cross-presentation capacity, regardless of tissue origin or culture conditions, suggesting that Sec22B is not critical for this process under these experimental conditions. Conversely, Biscari et al.67 showed that silencing Sec22B in DCs of C57BL/6 mice significantly hampers cross-presentation without impacting other pathways. Mice lacking Sec22B (Sec22B−/−) exhibit impaired activation of CD8+ T cells and, thus, struggle to control tumor progression. Additionally, silencing Sec22B in cancer xenografts mouse models resulted in a marked decrease in metastasis, autophagic activity, and cellular proliferation within the tumors. These findings suggest that Sec22B is crucial to the aggressive behavior of cancer cells. To date, no study has examined Sec61, Sec62, and Sec22B in an integrated framework within a single experimental or clinical context, making it difficult to rigorously assess whether these translocons act in a coordinated or interdependent manner comparable to other components of the APM. Evidence supporting their involvement in antigen handling has instead emerged from independent studies, most of which were conducted outside the BC setting, thereby limiting direct inference about their collective behavior in this disease. Taken together, these fragmented observations support a context-dependent model in which distinct cellular, metabolic, or microenvironmental conditions must be satisfied for individual Sec components to become functionally engaged—an abductive rationale that underpins the hypothesis synthesized in this review.

Recent studies have expanded our understanding of the role played by Sec61, Sec62, and Sec22B in the context of immuno-oncology.18,45,54,59,61 These translocons are known for their ability to facilitate the presentation of extracellular antigens through MHC-class I molecules, enabling recognition by CD8+ T cells. Their expression has been correlated with unfavorable prognostic outcomes, indicating the existence of a more intricate mechanism that is confined to specific characteristics14 which necessitate careful consideration.

Building on the integrated framework above, the available evidence does not support a model in which Sec61, Sec62, and Sec22B function as isolated or mutually exclusive modules, but instead points to a context-dependent convergence shaped by antigen properties76 and cellular state. All 3 translocons operate at ER-associated stages of antigen processing: Sec61 mediates the export of endocytosed antigens into the cytosol for proteasomal processing9,56,58, Sec62 enables selective, often TAP-independent reentry of processed peptides into the ER lumen29,63,65, and Sec22B orchestrates ER–phagosome fusion and vesicular trafficking that governs spatial and temporal compartmentalization of these events.68,71,72 This division of labor suggests functional specialization rather than redundancy, with pathway usage likely influenced by factors such as antigen size, peptide composition, intracellular antigen load, and microenvironmental cues, including ER stress.19,27,29 In this view, antigen presentation emerges from an adaptive network, in which Sec22B-dependent trafficking becomes particularly relevant under conditions of heightened demand or stress, while alternative routes may compensate in other settings, making it difficult to justify the action of these translocons outside their broader contextual interplay.

Future investigations of Sec translocons in antigen cross-presentation should prioritize the identification of genetic and expression alterations that may function as modulators or biomarkers of therapeutic responsiveness in BC, a domain that has received minimal attention to date. Emphasis should be placed on patient-derived and ex vivo analyses, where biologically meaningful patterns can be directly linked to clinical phenotypes. Stratifying Sec translocon alterations into immunologically responsive (“hot”) or nonresponsive (“cold”) states across individual tumor-specific or tumor-associated antigens may enable correlation with treatment response and survival using annotated clinical datasets. Importantly, such associations will require longitudinal study designs with serial sampling to capture dynamic changes during disease progression and therapy. While current knowledge is derived largely from preclinical in vitro and in vivo models, converging evidence supports the integration of genomic and transcriptomic profiling to establish a clinically actionable framework for understanding how Sec translocons influence tumor immune competence.