Pathobiology of thymic epithelial tumours and the treatment strategy based on immuno-oncological characteristics: a narrative review

Introduction

Thymic epithelial tumours (TETs) are relatively rare mediastinal tumours and include thymomas and thymic carcinomas (1). Thymomas exhibit a variety of histopathological findings that depend on the morphology of the tumour epithelial cells and the quantity of lymphocytes they contain. They are subclassified into types A, AB, B1, B2, and B3 according to the World Health Organization (WHO) classification (1). Most thymic carcinomas are squamous cell carcinomas. Thymic neuroendocrine tumours were previously classified as TETs and were often diagnosed as thoracic carcinoid tumours. Thymomas can be associated with various autoimmune diseases, such as myasthenia gravis (MG), pure red cell aplasia, and hypogammaglobulinemia (2,3). Cases of thymoma with positive anti-acetylcholine receptor (AChR) antibodies without MG and cases of MG developing after thymectomy have also been reported (4). However, the autoimmunogenicity of thymoma and the mechanisms underlying its association with autoimmune diseases remain unclear. In recent years, the development of immune checkpoint inhibitors (ICIs) for malignant tumours has been important, and clinical trials are also being conducted for thymic tumours (5,6). Since many thymomas are autoimmunogenic and often contain abundant lymphocytes within the tumour, the use of ICIs, which inherently carry the risk of autoimmune disease as an adverse event, requires careful consideration of the pathology of thymomas.

Thymic carcinomas, unlike thymomas, rarely present with autoimmune complications, and their treatment can be considered similar to that of other solid tumours. Recent clinical trials have demonstrated the efficacy of molecular targeted therapy using multi-kinase inhibitors and combined chemoimmunotherapy (7,8), thereby increasing the number of available treatment options.

The curative treatment for TETs is complete surgical resection. Recent advancements in minimally invasive surgery have been important, and technological innovations such as robotic-assisted surgery have provided substantial benefits to patients (9-11).

This review discusses the pathogenesis of thymoma and thymic carcinoma, which is considerably more complex than that of other cancers, and examines the treatment of these TETs based on a fundamental understanding of their immunopathology. We present this article in accordance with the Narrative Review reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-2025-1-72/rc).

Methods

A thorough search of the PubMed database was conducted for studies regarding the biology of TETs using a combination of the following terms: “thymoma”, “thymic carcinoma”, “myasthenia gravis”, “autoimmunity”, “T cell development”, “PD-L1”, “Transforming growth factor-β (TGF-β)”, “germinal centre”, “robotic surgery”, “immune check point inhibitor”, “molecular target”, and “biomarker”. Only articles in English were included in the present review (Table 1).

Pathobiology of TETs

T cell development in thymoma and its autoimmunogenicity

Thymomas are well known to be frequently associated with abundant immature T cells, which are similar to developing thymocytes in the normal infant thymus, namely CD4⁺CD8⁺ double-positive T cells (12,13). Such immature T cells are observed even in pleural or distant metastatic sites in thymoma patients (14), indicating potential T cell development within thymomas, supported by the functional neoplastic thymic epithelial cells (TECs). We previously showed T-cell maturation from CD3⁻CD4⁻CD8⁻ immature T cells into CD4⁺CD8⁺ T cells via CD3⁻CD4⁺CD8⁻ cells with in vitro reaggregation culture using isolated CD34⁺CD3⁻CD4⁻CD8⁻ T cell progenitors and primary culture neoplastic TECs (15). There is also variability in major histocompatibility complex (MHC) class II expression on neoplastic TECs, which plays a key role in normal T cell selection in the thymus, and the expression level is correlated with the degree of T-cell maturation (16). Such an alteration in the function of neoplastic TECs as stroma in the thymic environment could affect the positive and negative T cell selections in thymoma and might cause various autoimmune diseases, including MG. We propose the affinity/avidity model of the thymoma microenvironment, which could be the basic potential mechanism for its autoimmune comorbidities (Figure 1). Moderate impairment of MHC class II expression could induce inappropriate selection of autoreactive T cells, causing autoimmune diseases, whereas TECs with severe MHC class II downregulation can show neither the activity of T cell selection nor autoimmune behaviours.

Figure 1 Auto-immunogenicity of thymoma on the affinity/avidity model for T cell selection in the thymus. TCR-MHC, T cell receptor-major histocompatibility complex.

T cell characteristics in thymoma by WHO histological type

T cells within thymomas exhibit characteristic patterns that depend on the histological subtype. We previously reported that, in AB, B1, and B2 thymomas, the T-cell population is predominantly composed of CD4⁺CD8⁺ double-positive cells, similar to those observed in the normal thymus, whereas in type A and B3 thymomas, the proportion of CD4⁺CD8⁺ cells is low (17). Furthermore, we demonstrated that the amounts of T-cell receptor excision circles (TRECs), which can be detected in newly formed naïve T cells in the thymus, in CD4 and CD8 single-positive T cells are significantly higher in AB, B1, and B2 thymomas than in type A and B3 thymomas, and comparable to the normal thymus. Although CD8⁺ T cells are the main targets of ICIs, most intratumoral CD8⁺ T cells in AB, B1, and B2 thymomas appear to be thymocytes that have matured within the tumour, rather than tumour-infiltrating T cells. These results suggest a limited potential efficacy of immunotherapy in AB, B1, and B2 thymomas. Yamamoto et al. analysed T cells within thymomas and thymic carcinomas using flow cytometry and reported that type B3 thymomas and thymic carcinomas belonged to the “hot cluster”, characterized by prominent expression of Tim-3 and CD103 in CD4 and CD8 single-positive T cells. They also reported that marked enhancements in cytokine secretion and cytotoxicity induced by T cells on exposure to an anti-programmed cell death-1 (anti-PD-1) antibody were particularly evident in type B3 thymomas and thymic carcinomas (18,19). These findings suggest the potential utility of immunotherapeutic approaches for patients with type B3 thymomas and thymic carcinomas.

Molecular pathology of TETs

The molecular basis and pathogenesis of TETs remain uncertain due to the rarity of this disorder, and the associated abundant non-neoplastic T cells have complicated bulk molecular analyses in thymoma. Genetic alteration in TETs is unique compared with other malignancies. The GTF2I gene, a multifunctional phosphoprotein with roles in transcription and signal transduction, is found as a footprint in WHO type A and AB thymomas (20,21). Regarding potential tumour suppressor genes, chromosome 6 harbours frequent genetic aberrations, mainly loss of heterozygosity (LOH), detected with microsatellite analyses; these aberrations tend to increase according to the malignant characteristics of TETs (22,23). We found the genetic spectrum from low-grade thymoma to thymic carcinoma via high-grade thymoma in TETs. These results might suggest the molecular sequences against the distinct immunological differences between thymoma and thymic carcinoma. Interestingly, the HLA-DP, DQ, and DR loci are located on chromosome 6p.21.3. In addition, a unique KMT2A-MAML2 translocation is found in WHO type B2 and B3 thymomas, and YAP1-MAML2 translocation is found in metaplastic thymoma, which is a rare histological subtype of low-grade thymoma (24). A lack of medullary autoimmune regulator gene (AIRE) expression has been reported in thymoma, though its influence on the pathogenesis of autoimmune comorbidities remains unclear (25,26).

Programmed cell death-ligand 1 (PD-L1) expression on TETs

The evaluation of PD-L1 expression in TETs involves considerable complexity, with wide-ranging findings. PD-L1, the ligand for PD-1, is a key mediator of tumour immune evasion and is expressed on tumour cells. Because tumours exploit this pathway to escape attack by tumour-infiltrating lymphocytes (TILs), PD-L1-positive tumours are theoretically more capable of evading host immunity (27). Similarly, high-grade histological subtypes of TETs may express PD-L1 as part of their immune evasion strategy. However, since TETs arise from thymic epithelial tissue, interpretation of PD-L1 expression is complicated by the thymus’s own expression patterns: thymocytes express PD-1 during multiple maturation stages, and TETs regulate positive selection via PD-L1 and programmed cell death-ligand 2 (PD-L2) (28). PD-L1 is expressed broadly throughout the thymus, whereas PD-L2 expression is largely restricted to the medulla (29). In the normal thymus, PD-L1 expression can be detected from early life (Figure 2), and it may persist even after thymic involution (30). Thymomas have been reported to show higher PD-L1 expression rates than many other tumour types (31), likely reflecting their origin in the thymic epithelium.

Figure 2 Immunohistochemical staining for PD-L1 expression in the infant thymus at (A) low-power magnification (×100) and (B) high-power magnification (×400). PD-L1, programmed death-ligand 1.

Thymomas encompass diverse histological subtypes and exhibit considerable variability in PD-L1 expression. They are classified into low-grade Types A, AB, and B1, and the more aggressive B2 and B3 subtypes. Distinct PD-L1 expression profiles have been reported across these subtypes (30,32-37). Our data similarly demonstrated characteristic expression patterns (36). Specifically, PD-L1 expression was low in Type A/AB thymomas and high in Type B thymomas, findings largely consistent with previous reports. However, results regarding thymic carcinomas are less consistent. Several studies have reported higher PD-L1 expression in thymic carcinomas than in thymomas (38,39), whereas others have found the opposite results (30,32,33,35,36). This discrepancy likely reflects the marked histological heterogeneity of thymomas, differences in antibody specificity, and variable sample sizes. Notably, studies directly comparing Type B3 thymomas and thymic carcinoma demonstrated significantly higher PD-L1 expression in B3 thymomas. This conclusion was consistent across four antibody clones (40).

Several studies have investigated molecular mechanisms underlying PD-L1 expression in TETs. Umemura et al. reported that loss of CYLD function enhances IFN-γ-dependent PD-L1 expression via the STAT1/IRF1 axis, whereas tumour necrosis factor alpha (TNF-α) can induce PD-L1 independently of the NF-κB pathway (41). Arbour et al. found a significant association between high PD-1 expression and moderate to high levels of glucocorticoid-inducible tumour necrosis factor receptor (GITR) in high-grade TETs (42). Moreover, HDAC, a proposed prognostic factor in TETs, has been shown by immunohistochemistry to correlate positively with PD-L1 expression (43). PD-L1 expression has also been linked to epithelial-mesenchymal transition (EMT)-related markers, suggesting a potential role in predicting progression-free survival (PFS) (44).

Associations between PD-L1 expression and clinicopathologic features in TETs remain inconsistent. Regarding disease stage, several studies reported significant associations with advanced Masaoka-Koga (32,34,38,39) or Masaoka stages (33,45), whereas others found no correlations (36,44,46,47). With respect to age or sex, most studies found no associations with PD-L1 expression (32,33,35,36,39). Regarding MG comorbidity, most reports similarly found no association, though a few identified a positive correlation (35). Given that PD-L1 is highly expressed in Type B thymomas, which also show higher rates of MG, this relationship may be driven by the histological subtype. Several studies have also described increased PD-L1 expression following chemotherapy (32,44,46,48). Katsuya et al. reported that chemotherapy-induced immunogenic cell death activates dendritic cells, leading to T-cell stimulation and interferon-gamma (IFN-γ) production, which in turn induces PD-L1 expression on tumour cells (48).

The prognostic impact of PD-L1 expression in TETs is likewise controversial. Some studies have reported an association between high PD-L1 expression and a poor prognosis (36,37,45), whereas other research has linked high PD-L1 expression to good outcomes (42,49). Several other studies found no clear prognostic impact (34,38,39,46,47,50). In contrast, clinical trials have consistently shown that higher PD-L1 expression is associated with improved responses to ICIs, regardless of whether the tumour is a thymoma or thymic carcinoma (5,19,51). Collectively, these data support PD-L1 as a useful predictive biomarker for immunotherapy in TETs.

TGF-β as a biomarker in TETs

TGF-β is a pleiotropic cytokine with complex roles in tumour biology. Although it can function as a tumour suppressor in early oncogenesis, in established cancers, TGF-β often promotes the EMT, invasion, angiogenesis, and immunosuppression (52). It also modulates immune responses, fostering an immunosuppressive tumour microenvironment (53). However, the significance of TGF-β in TETs remains incompletely understood.

A recent study was the first to evaluate the clinical and biological significance of TGF-β1 expression in resected TETs (54). Immunohistochemical analysis showed high intratumoural TGF-β1 expression in 28.3% of cases, including 15.4% of thymic carcinomas and 30.4% of thymomas. Although no clear correlation with WHO histological subtype was observed, 70% of TETs with advanced Masaoka stage (III/IV) exhibited high TGF-β1 levels. Clinically, 5-year freedom from recurrence (FFR) was 95.1% in the low TGF-β1 expression group vs. only 58.1% in the high-expression group. Notably, high co-expression of TGF-β1 and PD-L1 conferred an even worse prognosis (5-year FFR 46.1%), and this combined expression emerged as an independent predictor of recurrence. Mechanistically, the same study demonstrated a positive correlation between intratumoral TGF-β1, phosphorylated Smad2/3, and PD-L1 on immunohistochemistry. In vitro, treatment of a thymic carcinoma cell line (55) with recombinant TGF-β1 induced a dose-dependent upregulation of PD-L1 mRNA and protein, accompanied by increased Smad2/3 phosphorylation. This is consistent with reports in human lung cancer cells showing that TGF-β1 upregulates PD-L1 via a Smad2-dependent mechanism (56). Taken together, these findings suggest that TGF-β1 drives immune evasion in TETs by enhancing PD-L1 expression through Smad signalling. Furthermore, patients whose tumours co-express high TGF-β1 and PD-L1 appear to be at higher risk of recurrence and might benefit from combined TGF-β/PD-L1 blockade.

Aside from the above, only one other study has examined TGF-β in unresectable advanced TET and demonstrated that a significantly higher proportion of thymic carcinomas (65.0%) exhibit high TGF-β1 expression compared with invasive thymomas (15.4%) (57). Moreover, in advanced disease, high TGF-β1 expression was associated with shorter median overall survival (29.5 vs. 62.9 months). Together with the findings in resectable tumours, this suggests that TGF-β1 is a predictor of a poor prognosis across all stages of TET, underscoring its critical role in tumour progression and recurrence. The difference between thymoma and thymic carcinoma for TGF-β expression is further topic to be solved.

From a therapeutic standpoint, targeting TGF-β has attracted considerable interest. One example is bintrafusp alfa (M7824), a bifunctional fusion protein that combines an anti-PD-L1 antibody with the extracellular domain of TGF-β receptor II. This agent is currently being evaluated in a phase II trial for relapsed TET (NCT04417660) (58). Early evidence suggests that dual TGF-β/PD-L1 blockade can overcome TGF-β-mediated immunosuppression and thereby enhance the efficacy of checkpoint inhibition. Furthermore, emerging evidence highlights the role of TGF-β in shaping the tumour microenvironment, notably by promoting angiogenesis and activating cancer-associated fibroblasts (CAFs) (52). Overall, these observations might support the view that TGF-β not only contributes to immune evasion, but also fosters a pro-tumorigenic mesenchymal microenvironment, underscoring its potential as both a biomarker and a therapeutic target. However, the clinical role of TGF-β has not been addressed in TETs. Further research would be warranted.

Germinal centre (GC) formation in TETs, surrounding thymus, and extrathymic tissue with MG potential

In MG, an association with abnormal thymic pathology has long been recognized. Anti-AChR antibodies have been reported to be produced in MG-associated hyperplastic thymuses in vitro (59). Ectopic GCs are often formed in the thymus of patients with anti-AChR antibody-positive MG, and thymic hyperplasia with ectopic GCs is observed in approximately 50–60% of patients with anti-AChR antibody-positive MG (60). GC is a specialized microenvironment in which activated B cells can mutate B cell receptors and undergo affinity maturation (61,62). In MG, ectopic GCs are thought to play an important role in the production of high-affinity anti-AChR antibodies. Ectopic GCs in the thymus typically form in the medulla, where AChR antigen-expressing mTECs and myoid cells are present and believed to trigger autoimmune responses leading to GC formation (63,64). It has been reported that the number of GCs correlates with anti-AChR antibody titres (65-67). In thymomas, we previously reported that ectopic GCs are more frequently observed in the medulla of the residual thymus in anti-AChR antibody-positive cases than in antibody-negative cases (60.7% vs. 9.8%) (65). Within the antibody-positive cases, GCs were significantly more frequently observed in younger patients and in thymuses with less involution. The loss of medullary structure associated with thymic involution may lead to a reduction in cells essential for GC formation, such as AChR antigen-expressing myoid cells, thereby hindering GC development. A randomized trial of thymectomy for MG without thymoma showed that thymectomy was not effective in patients over 50 years of age (68). This result suggests that resection of an age-related involuted thymus may not be therapeutically beneficial, and it raises the question of whether the extent of thymectomy should also be reconsidered in elderly patients with MG-associated thymoma.

Not only the adjacent thymus, but also the thymoma itself may contribute to the pathogenic process leading to anti-AChR antibody production. In the normal thymus, self-reactive T cells are excluded by negative selection in the thymic medulla and corticomedullary junction. In thymomas, T-cell maturation occurs similarly to the normal thymus; however, because of the reduced medullary architecture and the consequent absence of medullary TECs (mTECs) expressing autoimmune regulator (AIRE) and regulatory T cells (Tregs), self-reactive T cells are thought to survive without being eliminated (64,69). T cells that mature within thymomas exit to the peripheral blood and alter the peripheral T-cell repertoire by thymoma-derived autoreactive T-cells (70). Furthermore, recently, a population of neuromuscular antigen-expressing mTECs (nmTECs) has been identified within thymomas associated with MG, and these cells are believed to promote the generation of pathogenic autoantibodies (71). These findings suggest that disease mechanisms intrinsic to the tumour, independent of the adjacent thymus, may also exist. The immunological influence of thymectomy has been discussed with the risk of second malignancy and survival outcome (72,73). The negative impact of total thymectomy on postoperative outcome is still controversial. We should carefully consider the necessity of total thymectomy based on the pathological evidence and reported clinical outcomes with the risk of second malignancy. This issue should be investigated as a future challenge.

Management of TETs

Immunotherapy for TETs

In clinical trial reports of ICI therapy for TETs, Rajan et al. conducted a phase I trial of the anti-PD-L1 antibody avelumab in seven patients with relapsed thymoma (B1, n=1; B2, n=3; B3, n=3) and one patient with thymic carcinoma, all of whom had received at least one prior standard therapy (19). Confirmed partial responses were observed in 2 of 7 thymoma cases (B1, n=1; B3, n=1), whereas the patient with thymic carcinoma achieved stable disease. Grade ≥3 immune-related adverse events (irAEs) occurred in 5 of 8 patients (62.5%). Cho et al. reported a single-centre phase II study of the anti-PD-1 antibody pembrolizumab in 26 patients with thymic carcinoma and 7 patients with thymoma (B2, n=4; B2/3, n=3; B3, n=2) whose disease had progressed following at least one line of platinum-based chemotherapy (5). In this study, the overall response rate was 28.6% for thymomas and 19.2% for thymic carcinomas. Pembrolizumab was discontinued due to grade 3 or 4 irAEs in 5 patients with thymoma (71.4%) and 3 patients with thymic carcinoma (11.5%). A meta-analysis including 6 clinical trials summarized the ICI management in TETs with its significant higher risk of irAE in thymoma (74). Recently, the promising results of combined chemo-ICI regimens using carboplatin, paclitaxel and atezolizumab for thymic carcinoma was reported (6). These findings indicate that ICIs may induce irAEs at a high frequency in thymoma, not in thymic carcinoma, warranting careful consideration.

Immunological philosophy of robotic subxiphoid-optical thymectomy as a current standard minimally invasive surgery

The extent of thymus resection in treating TETs has long been a subject of discussion. Historically, the advantage of extended thymectomy (ET), which involves the en bloc resection of extracapsular fat tissue, was reported in patients with non-thymomatous MG (75). Based on this rationale, ET has been indicated for not only thymomatous MG patients, but also for patients with non-MG thymoma who test positive for anti-AChR antibodies, often at the institution’s or physician’s discretion. In the era preceding minimally invasive surgery, there was little debate regarding the extent of thymus resection, whether total or partial, in TETs, since the technical burden of total or ET via median sternotomy was limited. However, with the advent of thoracoscopic minimally invasive surgery, a significant difference in technical difficulty and operative duration became apparent between total and partial thymectomy (76). Subsequently, the introduction of robotic surgery has narrowed the technical gap between total and partial resection, leading to a shrinking discussion about the feasibility of partial resection. Notably, the surgical view and manipulation offered by robotic trans-subxiphoid thymectomy are similar or superior to those of conventional trans-sternal thymectomy (9,77). Furthermore, a high density of GCs in the cervical region has been reported in patients with MG (78). Although the cervical region remains technically challenging to access via conventional thoracoscopy, the use of multi-jointed robotic instruments facilitates more precise dissection. Consequently, robotic trans-subxiphoid thymectomy may offer a biological advantage in the surgical management of MG.

Inflammatory biomarkers in TETs

Systemic inflammation promotes tumour progression and is recognised as a hallmark of cancer (79). In TETs, the systemic inflammatory status can be evaluated using routine blood-based markers. In a study analysing perioperative peripheral blood parameters in resectable TETs, elevated preoperative leukocyte, neutrophil, and platelet counts were associated with significantly worse relapse-free survival, suggesting a positive association between the systemic inflammatory response and tumour progression (80). Of these markers, the neutrophil count (cut-off 4,450/µL) showed the strongest prognostic impact. Five-year relapse-free survival was 63.8% in the high-neutrophil group vs. 96.8% in the low-neutrophil group, and it also remained independently predictive. A composite risk score incorporating neutrophil count, stage, and histology improved prognostic stratification. Notably, neutrophil counts decreased after surgery, but rose again at tumour recurrence, indicating their potential utility as a dynamic tumour marker.

A high preoperative neutrophil-to-lymphocyte ratio (NLR) (cut-off 2.27) has also been linked to inferior survival, with particularly pronounced effects in tumour-node-metastasis (TNM) stage III thymoma, where disease-free survival was 0% vs. 66% in the low-NLR group (81). In a separate evaluation of multiple inflammatory indices, the NLR and platelet-to-lymphocyte ratio (PLR) demonstrated predictive value on receiver-operating characteristic (ROC) curve analysis, although only NLR remained significant on logistic regression; fibrinogen correlated with stage, but was not independently prognostic (82). In addition, an elevated C-reactive protein (CRP >1 mg/dL) was more frequently observed in thymic carcinoma and neuroendocrine tumours, whereas high lactate dehydrogenase (LDH >240 U/L) was associated with poorer disease-specific survival in thymic carcinoma (83). In thymic carcinoma, NLR, regardless of being analysed as a continuous variable or as a categorical measure (highest quartile >4.1), was significantly associated with recurrence and overall survival, whereas PLR and absolute neutrophil counts were not (84). These findings underscore the importance of histology-specific interpretation when applying inflammatory biomarkers to TETs.

Although tumour stage remains the dominant prognostic factor, available evidence indicates that elevated neutrophil counts, high NLR, and increased CRP and LDH levels reflect a protumour inflammatory milieu and may refine prognostic assessment of TETs. Prospective validation, assessment of dynamic biomarker changes, and studies exploring anti-inflammatory or immunomodulatory therapeutic approaches are warranted. In addition, the biological significance of inflammatory findings might be somewhat different with other malignancies, because of the autoimmunogenicity of TETs. In fact, clinical or preclinical inflammatory responses have been described in non-thymomatous MG patients (85). Thus, we have to understand the results with careful interpretation based on the immunological characteristics of TETs.

Immunoproteasome (IP) inhibition as a novel target therapy for TETs

The 26S proteasome is an ATP-dependent macromolecular protease that recognises ubiquitin-tagged substrates and orchestrates their degradation, thereby maintaining protein homeostasis and regulating processes such as cell-cycle progression, DNA replication, transcription, and stress responses (86). Three types of proteasome are recognised: the constitutive proteasome (CP), which mediates general protein turnover; the IP, whose inducible β1i, β2i, and β5i subunits are upregulated by interferon-γ and specialise in generating peptides for major histocompatibility complex class-I presentation (87); and the thymoproteasome (TP), which contains the β5t subunit encoded by PSMB11 and is expressed uniquely in cortical TECs to enable positive selection of CD8⁺ T cells (88). Upregulation of proteasome activity is a common feature of malignancies; IP subunits, particularly β5i (PSMB8), influence tumour antigenicity and micro-environmental interactions and have been linked to a poor prognosis in several cancers (87). Although β5t is used as a cortical marker in TETs (89), the significance of CP and IP expressions in TETs has been unclear.

A recent study addressed this gap by profiling proteasome expression and drug sensitivity in TETs (90). A chemical screen of 120 agents identified carfilzomib, an irreversible CP/IP inhibitor, as one of the most potent compounds against thymic carcinoma cell lines (55,91). Immunohistochemical analysis of 138 tumours showed heterogeneous UPS expression; high levels of PSMB5 (β5c) and PSMB8 (β5i) were enriched in advanced-stage disease and correlated with shorter PFS. Carfilzomib induced caspase-dependent apoptosis, endoplasmic-reticulum stress, and autophagy. Low-dose carfilzomib synergised strongly with BCL-2 family inhibitors, which have recently been proven to be strong inducers of apoptosis and emerged as novel therapeutic agents for thymic carcinoma (92), to enhance cell death. Mechanistic studies demonstrated that carfilzomib inhibits both CP and IP activities while sparing TP; interferon-γ upregulated PSMB8, enhancing drug sensitivity, whereas silencing PSMB8 or PSMB10 reduced sensitivity. Thymic squamous cell carcinomas showed characteristically higher PSMB8 expression than squamous carcinomas of the lung or head and neck, a notable distinction given the generally conserved molecular profiles across squamous cell carcinomas from different organs, and high PSMB8 expression predicted a better response to carfilzomib. These findings indicate that IP-targeted therapy may be particularly effective for TETs and that PSMB8 expression could serve as a biomarker for patient selection.

Clinical experience with proteasome inhibitors in other malignancies supports the development of this strategy in TETs. Bortezomib, a reversible CP/IP inhibitor, improved response rates and survival in multiple myeloma and paved the way for second-generation inhibitors (93). The irreversible inhibitor carfilzomib displays improved tolerability and activity in myeloma (93). In the phase III trial, adding carfilzomib to lenalidomide and dexamethasone extended median PFS from 17.6 to 26.3 months compared with lenalidomide/dexamethasone alone (hazard ratio 0.69) (94). Beyond haematological malignancies, pre-clinical studies show that carfilzomib inhibits proliferation, invasion, and migration of hepatocellular carcinoma cells by inducing cell-cycle arrest and upregulating GADD45α (95). Together with the new data for TETs, these results suggest that proteasome inhibition, particularly targeting the IP, is a promising, biomarker-guided therapeutic avenue for TETs

Conclusions

A fundamental understanding of pathobiology is crucial in the management of TETs. Since thymomas could be associated with autoimmunogenicity, the selection of immunotherapy as an oncological management must be performed with extreme caution. Given the potential immunological role of ectopic GCs, total or ET is required in thymoma patients presenting with autoimmunogenicity. Ultimately, robotic total thymectomy offers a reasonable and minimally invasive approach for thymoma and MG patients. We believe that the extremely interesting immunological, pathological, and oncological biology should be further challenged for more appropriate management in TETs patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-2025-1-72/rc

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-2025-1-72/prf

Funding: This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (Nos. 16K10705 and 23K19546), and a Uehara Memorial Foundation Research Fellowship, 2021 (to S.O.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-2025-1-72/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Tumours of the thymus. WHO Classification of Tumours 5th Ed. Thoracic Tumours. 2020. IARC, Lyon Cedex, France. Available online: https://publications.iarc.who.int/Book-And-Report-Series/Who-Classification-Of-Tumours/Thoracic-Tumours-2021
2. Hishida T, Asamura H, Yoshida K, et al. Clinical features and prognostic impact of coexisting autoimmune disease other than myasthenia gravis in resected thymomas: analysis of a Japanese multi-institutional retrospective database. Eur J Cardiothorac Surg 2021;59:641-9. [Crossref] [PubMed]
3. Nakajima J, Okumura M, Yano M, et al. Myasthenia gravis with thymic epithelial tumour: a retrospective analysis of a Japanese database. Eur J Cardiothorac Surg 2016;49:1510-5. [Crossref] [PubMed]
4. Yamada Y, Yoshida S, Iwata T, et al. Risk factors for developing postthymectomy myasthenia gravis in thymoma patients. Ann Thorac Surg 2015;99:1013-9. [Crossref] [PubMed]
5. Cho J, Kim HS, Ku BM, et al. Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial. J Clin Oncol 2019;37:2162-70. [Crossref] [PubMed]
6. Shukuya T, Asao T, Goto Y, et al. Activity and safety of atezolizumab plus carboplatin and paclitaxel in patients with advanced or recurrent thymic carcinoma (MARBLE): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2025;26:331-42. [Crossref] [PubMed]
7. Proto C, Manglaviti S, Lo Russo G, et al. STYLE (NCT03449173): A Phase 2 Trial of Sunitinib in Patients With Type B3 Thymoma or Thymic Carcinoma in Second and Further Lines. J Thorac Oncol 2023;18:1070-81. [Crossref] [PubMed]
8. Niho S, Sato J, Satouchi M, et al. Long-term follow-up and exploratory analysis of lenvatinib in patients with metastatic or recurrent thymic carcinoma: Results from the multicenter, phase 2 REMORA trial. Lung Cancer 2024;191:107557. [Crossref] [PubMed]
9. Shimomura M, Okada S, Furuya T, et al. Short-term outcomes of robotic subxiphoid-optical thymectomy. Surg Today 2025;55:205-10. [Crossref] [PubMed]
10. Rückert JC, Swierzy M, Ismail M. Comparison of robotic and nonrobotic thoracoscopic thymectomy: a cohort study. J Thorac Cardiovasc Surg 2011;141:673-7. [Crossref] [PubMed]
11. Deckarm R, Flury DV, Deckarm S, et al. Surgical management of thymic tumors: a narrative review with focus on robotic-assisted surgery. Mediastinum 2024;8:48. [Crossref] [PubMed]
12. Fujii Y, Hayakawa M, Inada K, et al. Lymphocytes in thymoma: association with myasthenia gravis is correlated with increased number of single-positive cells. Eur J Immunol 1990;20:2355-8. [Crossref] [PubMed]
13. Takeuchi Y, Fujii Y, Okumura M, et al. Accumulation of immature CD3-CD4+CD8- single-positive cells that lack CD69 in epithelial cell tumors of the human thymus. Cell Immunol 1995;161:181-7. [Crossref] [PubMed]
14. Inoue M, Okumura M, Fujii Y, et al. Immaturity of lymphocytes in the metastatic lesions of thymoma. Clin Immunol Immunopathol 1998;88:249-55. [Crossref] [PubMed]
15. Inoue M, Fujii Y, Okumura M, et al. Neoplastic thymic epithelial cells of human thymoma support T cell development from CD4-CD8- cells to CD4+CD8+ cells in vitro. Clin Exp Immunol 1998;112:419-26. [Crossref] [PubMed]
16. Inoue M, Okumura M, Miyoshi S, et al. Impaired expression of MHC class II molecules in response to interferon-gamma (IFN-gamma) on human thymoma neoplastic epithelial cells. Clin Exp Immunol 1999;117:1-7. [Crossref] [PubMed]
17. Furuya T, Ishihara S, Ogi H, et al. Characteristic differences in the abundance of tumor-infiltrating lymphocytes and intratumoral developing T cells in thymoma, with special reference to PD-1 expression. Cancer Immunol Immunother 2023;72:2585-96. [Crossref] [PubMed]
18. Yamamoto Y, Iwahori K, Funaki S, et al. Immunotherapeutic potential of CD4 and CD8 single-positive T cells in thymic epithelial tumors. Sci Rep 2020;10:4064. [Crossref] [PubMed]
19. Rajan A, Heery CR, Thomas A, et al. Efficacy and tolerability of anti-programmed death-ligand 1 (PD-L1) antibody (Avelumab) treatment in advanced thymoma. J Immunother Cancer 2019;7:269. [Crossref] [PubMed]
20. Petrini I, Meltzer PS, Kim IK, et al. A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors. Nat Genet 2014;46:844-9. [Crossref] [PubMed]
21. Feng Y, Lei Y, Wu X, et al. GTF2I mutation frequently occurs in more indolent thymic epithelial tumors and predicts better prognosis. Lung Cancer 2017;110:48-52. [Crossref] [PubMed]
22. Inoue M, Marx A, Zettl A, et al. Chromosome 6 suffers frequent and multiple aberrations in thymoma. Am J Pathol 2002;161:1507-13. [Crossref] [PubMed]
23. Inoue M, Starostik P, Zettl A, et al. Correlating genetic aberrations with World Health Organization-defined histology and stage across the spectrum of thymomas. Cancer Res 2003;63:3708-15.
24. Marx A, Belharazem D, Lee DH, et al. Molecular pathology of thymomas: implications for diagnosis and therapy. Virchows Arch 2021;478:101-10. [Crossref] [PubMed]
25. Ströbel P, Murumägi A, Klein R, et al. Deficiency of the autoimmune regulator AIRE in thymomas is insufficient to elicit autoimmune polyendocrinopathy syndrome type 1 (APS-1). J Pathol 2007;211:563-71. [Crossref] [PubMed]
26. Scarpino S, Di Napoli A, Stoppacciaro A, et al. Expression of autoimmune regulator gene (AIRE) and T regulatory cells in human thymomas. Clin Exp Immunol 2007;149:504-12. [Crossref] [PubMed]
27. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002;8:793-800. [Crossref] [PubMed]
28. Keir ME, Latchman YE, Freeman GJ, et al. Programmed death-1 (PD-1):PD-ligand 1 interactions inhibit TCR-mediated positive selection of thymocytes. J Immunol 2005;175:7372-9. [Crossref] [PubMed]
29. Liang SC, Latchman YE, Buhlmann JE, et al. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol 2003;33:2706-16. [Crossref] [PubMed]
30. Marchevsky AM, Walts AE. PD-L1, PD-1, CD4, and CD8 expression in neoplastic and nonneoplastic thymus. Hum Pathol 2017;60:16-23. [Crossref] [PubMed]
31. Möller K, Knöll M, Bady E, et al. PD-L1 expression and CD8 positive lymphocytes in human neoplasms: A tissue microarray study on 11,838 tumor samples. Cancer Biomark 2023;36:177-91. [Crossref] [PubMed]
32. Chen Y, Zhang Y, Chai X, et al. Correlation between the Expression of PD-L1 and Clinicopathological Features in Patients with Thymic Epithelial Tumors. Biomed Res Int 2018;2018:5830547. [Crossref] [PubMed]
33. Wei YF, Chu CY, Chang CC, et al. Different pattern of PD-L1, IDO, and FOXP3 Tregs expression with survival in thymoma and thymic carcinoma. Lung Cancer 2018;125:35-42. [Crossref] [PubMed]
34. Hakiri S, Fukui T, Mori S, et al. Clinicopathologic Features of Thymoma With the Expression of Programmed Death Ligand 1. Ann Thorac Surg 2019;107:418-24. [Crossref] [PubMed]
35. Song JS, Kim D, Kwon JH, et al. Clinicopathologic Significance and Immunogenomic Analysis of Programmed Death-Ligand 1 (PD-L1) and Programmed Death 1 (PD-1) Expression in Thymic Epithelial Tumors. Front Oncol 2019;9:1055. [Crossref] [PubMed]
36. Ishihara S, Okada S, Ogi H, et al. Programmed death-ligand 1 expression profiling in thymic epithelial cell tumors: Clinicopathological features and quantitative digital image analyses. Lung Cancer 2020;145:40-7. [Crossref] [PubMed]
37. Padda SK, Riess JW, Schwartz EJ, et al. Diffuse high intensity PD-L1 staining in thymic epithelial tumors. J Thorac Oncol 2015;10:500-8. [Crossref] [PubMed]
38. Katsuya Y, Fujita Y, Horinouchi H, et al. Immunohistochemical status of PD-L1 in thymoma and thymic carcinoma. Lung Cancer 2015;88:154-9. [Crossref] [PubMed]
39. Tiseo M, Damato A, Longo L, et al. Analysis of a panel of druggable gene mutations and of ALK and PD-L1 expression in a series of thymic epithelial tumors (TETs). Lung Cancer 2017;104:24-30. [Crossref] [PubMed]
40. Rouquette I, Taranchon-Clermont E, Gilhodes J, et al. Immune biomarkers in thymic epithelial tumors: expression patterns, prognostic value and comparison of diagnostic tests for PD-L1. Biomark Res 2019;7:28. [Crossref] [PubMed]
41. Umemura S, Zhu J, Chahine JJ, et al. Downregulation of CYLD promotes IFN-γ mediated PD-L1 expression in thymic epithelial tumors. Lung Cancer 2020;147:221-8. [Crossref] [PubMed]
42. Arbour KC, Naidoo J, Steele KE, et al. Expression of PD-L1 and other immunotherapeutic targets in thymic epithelial tumors. PLoS One 2017;12:e0182665. [Crossref] [PubMed]
43. Stergiou IE, Palamaris K, Levidou G, et al. PD-L1 Expression in Neoplastic and Immune Cells of Thymic Epithelial Tumors: Correlations with Disease Characteristics and HDAC Expression. Biomedicines 2024;12:772. [Crossref] [PubMed]
44. Funaki S, Shintani Y, Fukui E, et al. The prognostic impact of programmed cell death 1 and its ligand and the correlation with epithelial-mesenchymal transition in thymic carcinoma. Cancer Med 2019;8:216-26. [Crossref] [PubMed]
45. Yokoyama S, Miyoshi H, Nishi T, et al. Clinicopathologic and Prognostic Implications of Programmed Death Ligand 1 Expression in Thymoma. Ann Thorac Surg 2016;101:1361-9. [Crossref] [PubMed]
46. Weissferdt A, Fujimoto J, Kalhor N, et al. Expression of PD-1 and PD-L1 in thymic epithelial neoplasms. Mod Pathol 2017;30:826-33. [Crossref] [PubMed]
47. Owen D, Chu B, Lehman AM, et al. Expression Patterns, Prognostic Value, and Intratumoral Heterogeneity of PD-L1 and PD-1 in Thymoma and Thymic Carcinoma. J Thorac Oncol 2018;13:1204-12. [Crossref] [PubMed]
48. Katsuya Y, Horinouchi H, Asao T, et al. Expression of programmed death 1 (PD-1) and its ligand (PD-L1) in thymic epithelial tumors: Impact on treatment efficacy and alteration in expression after chemotherapy. Lung Cancer 2016;99:4-10. [Crossref] [PubMed]
49. Yokoyama S, Miyoshi H, Nakashima K, et al. Prognostic Value of Programmed Death Ligand 1 and Programmed Death 1 Expression in Thymic Carcinoma. Clin Cancer Res 2016;22:4727-34. [Crossref] [PubMed]
50. Enkner F, Pichlhöfer B, Zaharie AT, et al. Molecular Profiling of Thymoma and Thymic Carcinoma: Genetic Differences and Potential Novel Therapeutic Targets. Pathol Oncol Res 2017;23:551-64. [Crossref] [PubMed]
51. Giaccone G, Kim C, Thompson J, et al. Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol 2018;19:347-55. [Crossref] [PubMed]
52. Derynck R, Turley SJ, Akhurst RJ. TGFβ biology in cancer progression and immunotherapy. Nat Rev Clin Oncol 2021;18:9-34. [Crossref] [PubMed]
53. Travis MA, Sheppard D. TGF-β activation and function in immunity. Annu Rev Immunol 2014;32:51-82. [Crossref] [PubMed]
54. Nakazono C, Okada S, Tando S, et al. Transforming Growth Factor-β1 as a Biomarker of Malignant Behavior and PD-L1 Expression in Thymic Epithelial Tumors. Cancer Sci 2026;117:181-92. [Crossref] [PubMed]
55. Ehemann V, Kern MA, Breinig M, et al. Establishment, characterization and drug sensitivity testing in primary cultures of human thymoma and thymic carcinoma. Int J Cancer 2008;122:2719-25. [Crossref] [PubMed]
56. David JM, Dominguez C, McCampbell KK, et al. A novel bifunctional anti-PD-L1/TGF-β Trap fusion protein (M7824) efficiently reverts mesenchymalization of human lung cancer cells. Oncoimmunology 2017;6:e1349589. [Crossref] [PubMed]
57. Duan J, Liu X, Chen H, et al. Impact of PD-L1, transforming growth factor-β expression and tumor-infiltrating CD8+ T cells on clinical outcome of patients with advanced thymic epithelial tumors. Thorac Cancer 2018;9:1341-53. [Crossref] [PubMed]
58. Rajan A, Sivapiromrat AK, McAdams MJ. Immunotherapy for Thymomas and Thymic Carcinomas: Current Status and Future Directions. Cancers (Basel) 2024;16:1369. [Crossref] [PubMed]
59. Vincent A, Scadding GK, Thomas HC, et al. In-vitro synthesis of anti-acetylcholine-receptor antibody by thymic lymphocytes in myasthenia gravis. Lancet 1978;1:305-7. [Crossref]
60. Cron MA, Maillard S, Villegas J, et al. Thymus involvement in early-onset myasthenia gravis. Ann N Y Acad Sci 2018;1412:137-45. [Crossref] [PubMed]
61. Vinuesa CG, Linterman MA, Goodnow CC, et al. T cells and follicular dendritic cells in germinal center B-cell formation and selection. Immunol Rev 2010;237:72-89. [Crossref] [PubMed]
62. Victora GD, Nussenzweig MC. Germinal centers. Annu Rev Immunol 2012;30:429-57. [Crossref] [PubMed]
63. Roxanis I, Micklem K, McConville J, et al. Thymic myoid cells and germinal center formation in myasthenia gravis; possible roles in pathogenesis. J Neuroimmunol 2002;125:185-97. [Crossref] [PubMed]
64. Marx A, Yamada Y, Simon-Keller K, et al. Thymus and autoimmunity. Semin Immunopathol 2021;43:45-64. [Crossref] [PubMed]
65. Furuya T, Tando S, Ogi H, et al. Distribution of Ectopic Germinal Centers in Thymic Epithelial Tumors and Their Relationship With Thymic Involution. Cancer Sci 2025;116:3209-19. [Crossref] [PubMed]
66. Lefeuvre CM, Payet CA, Fayet OM, et al. Risk factors associated with myasthenia gravis in thymoma patients: The potential role of thymic germinal centers. J Autoimmun 2020;106:102337. [Crossref] [PubMed]
67. Truffault F, de Montpreville V, Eymard B, et al. Thymic Germinal Centers and Corticosteroids in Myasthenia Gravis: an Immunopathological Study in 1035 Cases and a Critical Review. Clin Rev Allergy Immunol 2017;52:108-24. [Crossref] [PubMed]
68. Wolfe GI, Kaminski HJ, Aban IB, et al. Randomized Trial of Thymectomy in Myasthenia Gravis. N Engl J Med 2016;375:511-22. [Crossref] [PubMed]
69. Willcox N, Leite MI, Kadota Y, et al. Autoimmunizing mechanisms in thymoma and thymus. Ann N Y Acad Sci 2008;1132:163-73. [Crossref] [PubMed]
70. Hoffacker V, Schultz A, Tiesinga JJ, et al. Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease. Blood 2000;96:3872-9.
71. Yasumizu Y, Ohkura N, Murata H, et al. Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma. Nat Commun 2022;13:4230. [Crossref] [PubMed]
72. Kooshesh KA, Foy BH, Sykes DB, et al. Health Consequences of Thymus Removal in Adults. N Engl J Med 2023;389:406-17. [Crossref] [PubMed]
73. Resio BJ, Canavan M, Caturegli G, et al. Mortality Risk and Cause of Death Associated With Removal of the Adult Thymus: Analysis of the U.S. Thymoma Population. J Thorac Oncol 2026;21:186-94.
74. Remon J, Villacampa G, Facchinetti F, et al. Immune checkpoint blockers in patients with unresectable or metastatic thymic epithelial tumours: A meta-analysis. Eur J Cancer 2023;180:117-24. [Crossref] [PubMed]
75. Masaoka A, Monden Y. Comparison of the results of transsternal simple, transcervical simple, and extended thymectomy. Ann N Y Acad Sci 1981;377:755-65. [Crossref] [PubMed]
76. Inoue M, Yamamoto H, Okada Y, et al. Perioperative outcomes of minimally invasive surgery for large malignant thymic epithelial tumors and for total thymectomy. Surg Today 2023;53:1089-99. [Crossref] [PubMed]
77. Park JH, Na KJ, Kang CH, et al. Robotic subxiphoid thymectomy versus lateral thymectomy: a propensity score-matched comparison. Eur J Cardiothorac Surg 2022;62:ezac288. [Crossref] [PubMed]
78. Shigemura N, Shiono H, Inoue M, et al. Inclusion of the transcervical approach in video-assisted thoracoscopic extended thymectomy (VATET) for myasthenia gravis: a prospective trial. Surg Endosc 2006;20:1614-8. [Crossref] [PubMed]
79. Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov 2022;12:31-46. [Crossref] [PubMed]
80. Okada S, Shimomura M, Tsunezuka H, et al. High Neutrophil Count as a Negative Prognostic Factor for Relapse in Patients with Thymic Epithelial Tumor. Ann Surg Oncol 2020;27:2438-47. [Crossref] [PubMed]
81. Muriana P, Carretta A, Ciriaco P, et al. Assessment of the prognostic role of neutrophil-to-lymphocyte ratio following complete resection of thymoma. J Cardiothorac Surg 2018;13:119. [Crossref] [PubMed]
82. Janik S, Raunegger T, Hacker P, et al. Prognostic and diagnostic impact of fibrinogen, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio on thymic epithelial tumors outcome. Oncotarget 2018;9:21861-75. [Crossref] [PubMed]
83. Valdivia D, Cheufou D, Fels B, et al. Potential Prognostic Value of Preoperative Leukocyte Count, Lactate Dehydrogenase and C-Reactive Protein in Thymic Epithelial Tumors. Pathol Oncol Res 2021;27:629993. [Crossref] [PubMed]
84. Yuan ZY, Gao SG, Mu JW, et al. Prognostic value of preoperative neutrophil-lymphocyte ratio is superior to platelet-lymphocyte ratio for survival in patients who underwent complete resection of thymic carcinoma. J Thorac Dis 2016;8:1487-96. [Crossref] [PubMed]
85. Huda R. Inflammation and autoimmune myasthenia gravis. Front Immunol 2023;14:1110499. [Crossref] [PubMed]
86. Bard JAM, Goodall EA, Greene ER, et al. Structure and Function of the 26S Proteasome. Annu Rev Biochem 2018;87:697-724. [Crossref] [PubMed]
87. Tripathi SC, Vedpathak D, Ostrin EJ. The Functional and Mechanistic Roles of Immunoproteasome Subunits in Cancer. Cells 2021;10:3587. [Crossref] [PubMed]
88. Ohigashi I, Ohte Y, Setoh K, et al. A human PSMB11 variant affects thymoproteasome processing and CD8+ T cell production. JCI Insight 2017;2:e93664. [Crossref] [PubMed]
89. Yamada Y, Tomaru U, Ishizu A, et al. Expression of proteasome subunit β5t in thymic epithelial tumors. Am J Surg Pathol 2011;35:1296-304. [Crossref] [PubMed]
90. Okada S, Benter L, Schrell L, et al. Proteasome inhibition as a potential therapeutic target in thymic cancer. Cell Death Dis 2025;16:885. [Crossref] [PubMed]
91. Alberobello AT, Wang Y, Beerkens FJ, et al. PI3K as a Potential Therapeutic Target in Thymic Epithelial Tumors. J Thorac Oncol 2016;11:1345-56. [Crossref] [PubMed]
92. Müller D, Mazzeo P, Koch R, et al. Functional apoptosis profiling identifies MCL-1 and BCL-xL as prognostic markers and therapeutic targets in advanced thymomas and thymic carcinomas. BMC Med 2021;19:300. [Crossref] [PubMed]
93. Shah JJ, Orlowski RZ. Proteasome inhibitors in the treatment of multiple myeloma. Leukemia 2009;23:1964-79. [Crossref] [PubMed]
94. Avet-Loiseau H, Fonseca R, Siegel D, et al. Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma. Blood 2016;128:1174-80. [Crossref] [PubMed]
95. Chen M, Chen X, Shui Y, et al. Carfilzomib inhibits the progression of hepatocellular cancer by upregulating GADD45α expression. Oncol Lett 2025;29:208. [Crossref] [PubMed]