XPO1 is a ubiquitously expressed protein in eukaryotic cells. First identified in yeast, it has since been shown to mediate the nuclear export of hundreds of proteins (99). Studies of the natural compound leptomycin B (LMB), an inhibitor of XPO1, facilitated the identification of XPO1 cargo proteins. Among all exportins, XPO1 uniquely exports a broad spectrum of biologically important proteins, including tumour suppressors and growth regulators such as p53, p21 and FOXO, as well as key signalling molecules involved in the PI3K/AKT, Wnt/β-catenin, activator protein-1 and NF-κB pathways (100). Mechanistically, XPO1 inhibitors promote the nuclear retention of tumour suppressor proteins, thereby restoring their function. Even when a specific tumour suppressor, such as p53, is mutated or inactive, the abnormal accumulation of multiple tumour suppressors and growth-inhibitory factors within the nucleus can overwhelm cellular defence mechanisms and trigger programmed cell death (101). This class of inhibitors targets the cysteine residue Cys528 within the NES-binding groove of XPO1, preventing nuclear export of regulatory molecules and suppressing cell proliferation (100,102).

Research on nuclear export inhibitors began with LMB, a naturally occurring antifungal compound and the first identified XPO1 inhibitor (100). Similar to several subsequently developed compounds, LMB binds covalently to the Cys528 residue; however, its clinical development was discontinued because of severe dose-limiting gastrointestinal toxicity (89). Other naturally occurring XPO1 inhibitors include ratjadone C, anguinomycin and goniothalamin (100). Curcumin has also been reported to inhibit XPO1 by covalently binding to Cys528, resulting in nuclear accumulation of cargo proteins such as forkhead box protein O1 (FOXO1) (103). Although curcumin suppresses cell proliferation, its efficacy appears to be lower than that of synthetic XPO1 inhibitors (104).

The limitations of LMB prompted the development of synthetic compounds with improved safety profiles, most notably the selective inhibitors of nuclear export (SINEs). This group includes Selinexor (KPT-330), Verdinexor (KPT-335), KPT-185, KPT-251 and KPT-276. Similar to LMB, these compounds target the Cys528 residue of XPO1, but their interaction is reversible (Fig. 3A and B) (100). This reversibility reduces toxicity while maintaining anticancer activity. Selinexor is the most clinically advanced SINE and has been evaluated in >40 clinical trials across over 10 cancer types, including gynaecological malignancies (105). These studies ultimately led to approval by the Food and Drug Administration (FDA) for penta-refractory multiple myeloma (102). Verdinexor has also been investigated for treating viral infections, particularly influenza (106). Although compounds such as KPT-185 have demonstrated promising activity in vitro, their clinical development has been limited by unfavourable pharmacokinetic properties (107).

CBS9106, also known as felezonexor or SL-801, represents a distinct class of synthetic XPO1 inhibitors with dual mechanisms of action. In addition to reversibly inhibiting XPO1 and inducing apoptosis, this orally bioavailable compound markedly reduces XPO1 protein levels without affecting corresponding mRNA expression (108). XPO1 degradation occurs through the Cullin-RING ligase system and the neddylation pathway. Understanding this mechanism matters because it suggests that CBS9106 may show antagonistic interactions when combined with neddylation inhibitors or proteasome inhibitors (109). At present, no studies have specifically evaluated CBS9106 in gynaecological cancers. The CBS9106 derivative S109 is currently under development because it is simpler and more cost-effective to synthesize, facilitating large-scale production (110).

The preclinical and clinical success of XPO1-targeted therapies has stimulated the development of nuclear import inhibitors. Although this field remains at an early stage, targeting importins has shown considerable promise, with several small-molecule inhibitors already demonstrating anticancer activity in preclinical studies. In contrast to XPO1 inhibitors, which uniformly target the well-characterised NES-binding pocket, the binding sites and mechanisms of action of several nuclear import inhibitors remain incompletely understood.

Nuclear import inhibitors can be broadly classified into two groups: Direct importin inhibitors, which target the transport receptor itself, and cargo-specific inhibitors, which prevent the import machinery from recognizing individual cargo proteins (102). Direct importin inhibitors aim to disrupt the core nuclear transport apparatus. For example, the FDA-approved antiparasitic drug ivermectin binds the importin α/β1 heterodimer and blocks the nuclear import of viral proteins, including HIV-1 integrase, dengue virus NS5 and influenza virus proteins, thereby exerting broad-spectrum antiviral activity. However, this mechanism also affects host signalling pathways, including the HIF-1α pathway (73,111). The pleiotropic effects of importin inhibition are particularly relevant in cancer, as numerous oncogenic transcription factors and signalling mediators depend on importin-mediated nuclear translocation to exert their tumour-promoting functions.

In cancer cells, ivermectin binds importin β1 and inhibits nuclear transport (Fig. 3C and D). This prevents activated ERK5 from entering the nucleus, retaining it in the cytoplasm and inhibiting its pro-proliferative activity (112). Given the recognised role of ERK5 signalling in cell proliferation, survival and therapeutic resistance, including in gynaecological malignancies, these findings provide a mechanistic basis for targeting nuclear import pathways in cancer treatment (113,114). Similarly, the synthetic compound importazole directly targets importin β1 and impairs cargo transport by disrupting its interaction with RanGTP (115-117). This mechanism was first demonstrated for the importin β1 inhibitor karyostatin 1A, described in 2010, which prevents dissociation of the importin β1/importin α/cargo complex within the nucleus and thereby blocks classical nuclear import (118). Dissociation of this complex is essential for successful transport because it ensures cargo release within the nucleus rather than its return to the cytoplasm alongside the transport receptor. More recently, synthetic compounds such as INI-43 and INI-60, identified through in silico screening approaches (119), have further demonstrated the therapeutic potential of this strategy. INI-43 inhibits cancer cell growth and induces G2/M cell-cycle arrest by preventing nuclear import of pro-survival proteins, including NF-κB (120,121).

Aberrant activation of NF-κB has been extensively documented in ovarian cancer, where it contributes to chemoresistance, stemness, metastatic progression and survival signalling (122). Dysregulated NF-κB signalling has also been implicated in endometrial carcinoma and other endometrial disorders, linking this pathway to multiple gynaecological malignancies (123). Nevertheless, caution is warranted when extrapolating these findings to gynaecological cancers. Although dysregulation of NF-κB and ERK5 signalling is a recognised feature of gynaecological tumour biology, most mechanistic and efficacy studies involving ivermectin, importazole, INI-43 and INI-60 have been performed in non-gynaecological malignancies, including glioblastoma, oesophageal cancer and haematological cancers (120,124-127), or in preliminary cell-line models (120). Direct validation in disease-specific gynaecological models, particularly primary ovarian and endometrial tumours, patient-derived xenografts and clinical studies, remains lacking and represents an important area for future research.

In contrast to broadly acting importin inhibitors, cargo-specific inhibitors offer a more selective therapeutic approach by binding directly to the NLS of a specific cargo protein. This prevents cargo recognition by the import machinery and may reduce off-target toxicity (Fig. 4A and B). Examples include the corticosteroids budesonide and flunisolide, which bind the NLS of HIV-1 integrase and block its importin α/β1-mediated nuclear import. Mifepristone exerts a similar effect on HIV-1 integrase, although its clinical development was discontinued (128,129). Another example is the retinoid 4-HPR (fenretinide), which selectively disrupts the NS5/importin α/importin β1 interaction in flaviviruses, thereby inhibiting dengue and Zika virus infection without disturbing essential host nuclear import pathways (130). Although most cargo-specific inhibitors have been developed in antiviral settings, their mechanism of action is attractive for cancer therapy because it enables selective inhibition of oncogenic nuclear signalling while potentially minimising systemic toxicity.

An increasing number of studies have explored cargo-specific nuclear import inhibitors in cancer treatment (131-133). Collectively, current evidence suggests that although direct importin inhibitors provide potent, broad-spectrum activity, cargo-specific approaches may offer greater selectivity and reduced toxicity (102). Taken together, these findings support nuclear import inhibition as a mechanistically rational, albeit largely preclinical, therapeutic strategy that merits further investigation alongside the more clinically advanced nuclear export inhibitors.

However, the literature on cargo-specific nuclear import inhibitors in gynaecological cancers remains limited. Although this approach offers potential to avoid the toxicities associated with global inhibition of nucleocytoplasmic transport, most validated cargo-specific inhibitors, including budesonide, flunisolide and fenretinide, currently target viral proteins rather than oncogenic drivers relevant to ovarian, cervical or endometrial cancers (124). Future research should therefore focus on identifying critical nuclear localisation sequences within key gynaecological oncogenes to facilitate the development of tumour-specific nuclear import inhibitors and address this important translational gap.

In gynaecological cancers, particularly endometrial and ovarian cancers, several compounds targeting nuclear transport pathways have shown notable anticancer effects. Among nuclear export inhibitors, Selinexor has shown clinically meaningful activity in endometrial cancer. In the phase III SIENDO trial, a prespecified subgroup analysis demonstrated that Selinexor significantly prolonged progression-free survival (PFS) in patients with TP53 wild-type tumours, with a median PFS of 28.4 months compared with 5.2 months for placebo [hazard ratio 0.44; 95%; confidence interval (CI), 0.27-0.73; nominal P=0.0005]. These results support Selinexor as a biomarker-driven therapeutic strategy beyond its current FDA approval in hematologic malignancies. However, the authors note two main limitations of the SIENDO trial: A low number of patients with TP53-wt (113) and that certain patients (in both the Selinexor and placebo groups) discontinued before completing treatment. Given the fact that analysis was prespecified and the primary endpoint in the intent-to-treat population was not met, the subgroup analysis is exploratory, and the results are not conclusive. Additionally, >94% of patients were white and had endometrioid carcinoma; thus, the results do not reflect diverse populations and rare subtypes of endometrial cancer. As the study evaluated Selinexor in pretreated patients who previously received chemotherapy, the efficacy of Selinexor in untreated patients remains unknown. The SIENDO trial motivated the subsequent XPORT-EC-042 trial [NCT05611931, registered (first posted) at ClinicalTrials.gov 2022-11-10] (134). Although this study also focuses on pretreated patients with TP53-wt, the group size is approximately twice as large (276 participants), and the distribution between treatment arms is more balanced (1:1 Selinexor vs. placebo compared with 2:1 in the SIENDO trial). Selinexor also demonstrated activity in heavily pretreated ovarian and endometrial cancers. In an open-label, single-arm phase II study, median PFS was 2.6 months in ovarian cancer and 2.8 months in endometrial cancer patients treated with Selinexor (135). Similar to the SIENDO trial, this study also included previously pretreated patients; the groups differed in size and were relatively small (66 patients with ovarian cancer, 23 patients with endometrial cancer and 25 patients with cervical cancer). The authors assessed treatment response in 98 of 114 patients, and the absence of a placebo group limits direct comparison with other clinical trials. Although the authors performed circulating tumour cell analysis to assess treatment outcome, the subset of patients was small (31 patients with ovarian cancer, 8 patients with endometrial cancer and 6 patients with cervical cancer), so the findings are preliminary. The modest PFS and their differences in ovarian, endometrial and cervical cancer could be explained by a small sample size and different numbers of patients with highly resistant platinum-refractory tumours in the groups. The authors also note that Selinexor may yield better outcomes in combination with other treatment modalities (radiation therapy, targeted therapy or immunotherapy), especially because combination results in preclinical models (cell lines and mice) are promising (136-138). Identifying biomarkers to predict sensitivity to Selinexor in patients with gynaecological cancer could also improve outcomes. In platinum-resistant ovarian cancer models, XPO1 inhibition restored platinum sensitivity and induced apoptosis independently of p53 status (77). By contrast, among nuclear import inhibitors, ivermectin and the structurally related compounds INI-60 and INI-43 have shown anticancer activity by inhibiting importin β1, with selective cytotoxicity observed in cervical cancers (73,120,121). Ivermectin alone inhibited ovarian cancer growth by inducing cell cycle arrest and caspase-dependent apoptosis (139). Additionally, ivermectin showed importin β1-dependent antitumor activity in epithelial ovarian cancer, highlighting its potential for drug repurposing in this setting (73). Other compounds with anticancer effects in gynaecological cancers include budesonide, which has demonstrated antitumor activity in ovarian cancer cells (140), and fenretinide, which reduces viability and induces apoptosis in endometrial cancer Ishikawa cells in a dose-dependent manner (131). Notably, the effects of fenretinide were independent of retinoic acid receptor signalling and appeared to be mediated by increased retinol uptake via stimulated by retinoic acid 6 (STRA6), as silencing STRA6 notably reduced apoptosis. In vivo, intraperitoneal fenretinide treatment effectively suppressed tumour growth in mice bearing Ishikawa-derived endometrial tumours (131).

Conventional chemotherapies disrupt fundamental cellular processes, such as DNA replication and cell proliferation. However, they cannot distinguish between malignant and healthy cells, often resulting in substantial toxicity. By contrast, targeted therapies selectively inhibit cancer-associated pathways that normal cells depend on less. Nevertheless, dose-limiting toxicities and the emergence of drug resistance can compromise therapeutic efficacy. Consequently, combination therapy is frequently favoured over monotherapy. By concurrently targeting multiple oncogenic pathways, combination regimens may overcome resistance mechanisms that limit the effectiveness of both conventional and emerging anticancer agents (141). Furthermore, identifying synergistic or additive drug interactions may allow dose reduction without compromising therapeutic efficacy, thereby decreasing the frequency and severity of adverse effects (142).

Among gynaecological malignancies, particularly ovarian and cervical cancers, this strategy has shown considerable promise. Regarding nuclear import inhibition, ivermectin has shown importin β1-dependent antitumour activity in epithelial ovarian cancer, suppressing proliferation and inducing apoptosis by increasing expression of p21, p27 and Bax (73). Ivermectin also exhibited synergistic activity with paclitaxel in chemoresistant epithelial ovarian cancer models (143), while nanoparticle-based formulations have been investigated in combination with pitavastatin to improve therapeutic outcomes in ovarian cancer (144). In addition, ivermectin notably enhanced cisplatin efficacy in a dose-dependent manner. In xenograft mouse models, ivermectin monotherapy suppressed tumour growth, whereas combination treatment with cisplatin completely reversed tumour progression without observable toxicity at pharmacologically relevant concentrations (139). In cervical cancer, the nuclear import inhibitor INI-43 showed synergistic cytotoxicity with cisplatin by activating the p53 and NF-κB signalling pathways, highlighting its potential to improve outcomes in cisplatin-resistant disease and reduce treatment-related toxicity through dose reduction (145).

Conversely, selinexor, a nuclear export inhibitor, has demonstrated encouraging clinical activity in combination with weekly paclitaxel in ovarian cancer, with manageable toxicity and support for further evaluation in randomised trials. In the intention-to-treat population, the combination achieved a median PFS of 6.7 months (95% CI, 3.3-10.7 months) (146). Moreover, selinexor showed synergistic activity when combined with the PARP inhibitor olaparib, reducing DNA repair protein expression, increasing tumour suppressor expression and enhancing tumour cell death in ovarian cancer models (138).

The principal genetic resistance mechanism identified across multiple preclinical models involves substitution of XPO1 cysteine 528 with serine (C528S) (147). This single amino acid substitution eliminates the reactive thiol group of Cys528, rendering the binding pocket chemically inert to the covalent interaction required for SINE-mediated inhibition (148). Cells engineered to express the XPO1-C528S mutant display complete resistance to Selinexor, as demonstrated by the continued cytoplasmic localisation of critical XPO1 cargo proteins, such as RanBP1, following treatment. These findings indicate that the C528S mutation is sufficient to preserve the oncogenic nuclear export activity required for cellular survival despite drug exposure (149).

Notably, this resistance mechanism behaves dominantly. Experimental modelling using CRISPR/Cas9 genome editing demonstrated that a heterozygous C528S mutation confers a resistance phenotype comparable to that observed in homozygous mutant cells (150). In heterozygous cells, although the wild-type XPO1 allele remains susceptible to Selinexor inhibition, the mutant allele continues to produce fully functional XPO1 protein capable of exporting tumour suppressor proteins (TSPs) from the nucleus. This residual export activity is sufficient to maintain essential nucleocytoplasmic transport processes and to keep nuclear TSP concentrations, including RanBP1, below the threshold required to induce effective apoptosis. Consequently, a single mutational event may be sufficient to negate the therapeutic activity of SINE compounds, representing an efficient escape mechanism for cancer cells. Furthermore, because both first-generation (Selinexor) and second-generation (KPT-8602) SINE compounds depend on covalent binding to Cys528, this mutation confers cross-resistance to both classes of inhibitors (151).

The XPO1-C528S mutation has also been implicated in resistance to the novel XPO1 inhibitor S109 in ovarian cancer cells. In cells expressing the mutant protein, S109 failed to induce significant nuclear accumulation of the tumour suppressor proteins Foxo1 and p27, a key component of its mechanism of action. Moreover, XPO1-C528S-expressing cells resisted the growth-inhibitory effects of S109 at the tested concentrations, whereas cells expressing wild-type XPO1 showed significant growth suppression (152). However, no published clinical studies have established a role for the XPO1-C528S mutation as a mechanism of resistance to XPO1 inhibitors in patients with gynaecological cancers. Thus, the significance of this mutation remains primarily mechanistic rather than clinical, serving as a model of target-mediated resistance rather than an established acquired biomarker.

Not all XPO1 mutations confer resistance to SINE compounds. Clinical genomic profiling has identified alternative XPO1 alterations in gynaecological malignancies. Among these, the XPO1-R749Q mutation is a recurrent variant enriched in endometrial cancer, accounting for ~50% of reported R749Q cases in solid tumours and frequently co-occurring with polymerase epsilon hotspot mutations. This variant is particularly prevalent in tumours with high tumour mutational burden and may confer resistance to conventional topoisomerase I inhibitors while retaining sensitivity to Selinexor-based combination therapies (153).

In addition to XPO1 alterations, resistance to SINE compounds in gynaecological malignancies may be influenced by tissue-specific molecular characteristics, particularly the high prevalence of TP53 mutations. Results from the Phase III SIENDO trial demonstrated that the efficacy of Selinexor maintenance therapy in advanced or recurrent endometrial cancer is strongly dependent on molecular subtype. Patients with TP53 wild-type tumours experienced substantially prolonged median PFS, whereas those with TP53-mutant tumours derived no notable benefit from treatment (154,155). Mechanistically, Selinexor promotes nuclear accumulation of wild-type p53 and restores its tumour-suppressive functions, leading to cell-cycle arrest and apoptosis. By contrast, tumours harbouring dysfunctional mutant p53 are less likely to benefit from this therapeutic mechanism (156).

Several agents that restore p53 function are currently under clinical investigation and may enhance the efficacy of Selinexor. APR-246, a small-molecule p53 reactivator, is undergoing clinical evaluation for high-grade serous ovarian carcinoma and has shown particularly promising activity in tumours with low CIP2A expression (157). APR-246 has also been reported to restore sensitivity to DNA-damaging agents in both established and primary ovarian cancer cells with acquired drug resistance (158). Another p53-reactivating agent, COTI-2, successfully completed a Phase I trial in recurrent gynaecological cancers (NCT02433626; first registered on ClinicalTrials.gov on 5 May 2015) and has received FDA orphan drug designation for ovarian cancer treatment (159). A total of ~3% of ovarian tumours harbour the TP53 Y220C mutation, for which the mutant p53-targeting agent PC14586 has demonstrated encouraging clinical activity (160).

Despite their potential, none of these p53-restoring compounds have yet been evaluated in combination with nuclear export inhibitors. To date, only combinations of Selinexor and PARP inhibitors have demonstrated preclinical efficacy, although not specifically in TP53-mutant gynaecological cancers. These studies focused primarily on therapeutic synergism rather than mechanisms of Selinexor resistance. In ovarian cancer, screening of 688 compounds identified the PARP inhibitor Olaparib as the most synergistic partner for Selinexor, a finding subsequently validated in both cell-line and mouse models. Combination treatment reduced DNA repair protein expression while increasing tumour suppressor protein levels. However, these experiments used the A2780 cell line, which carries wild-type TP53; therefore, the observed synergy cannot be attributed to restoration of mutant p53 function (138).

The synergistic interaction between Selinexor and Olaparib was also confirmed in the OVCAR5 mouse model; however, the TP53 status of OVCAR5 cells remains controversial, with conflicting reports describing the cell line as either wild-type or functionally deficient. Notably, the Selinexor-Olaparib combination was effective in the TP53-mutant breast cancer cell lines MDA-MB-468 and MDA-MB-436, inducing cell-cycle arrest and cell death in vitro and suppressing tumour growth in xenograft models in vivo (161). Although that study did not focus on TP53 mutation status, these findings provide preclinical evidence supporting the potential utility of Selinexor-based combination therapies in TP53-mutant cancers.

Beyond structural alterations in the XPO1 target protein, resistance mechanisms involving drug efflux and global cellular adaptation also play important roles in limiting the efficacy of SINE compounds in several tumour types.

Multidrug resistance (MDR) is frequently associated with overexpression of ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP). These membrane-bound transporters function as active efflux pumps, utilising ATP hydrolysis to export a broad range of structurally diverse substrates, including several hydrophobic small-molecule chemotherapeutic agents, from the cell (162). In gynaecological malignancies, including cervical and ovarian cancer, MDR is commonly mediated by overexpression of drug efflux pumps, particularly P-gp and MRP1, which reduce intracellular drug accumulation and consequently diminish therapeutic efficacy (163-165).

As SINE compounds are small, hydrophobic molecules, they are recognised and transported by ABC efflux pumps (166). Overexpression of P-gp, often resulting from gene amplification or transcriptional and epigenetic alterations, markedly reduces intracellular drug accumulation and lowers intracellular SINE concentrations (162). This pharmacokinetic mechanism provides an alternative route to resistance that does not require genetic alteration of the XPO1 target. Consequently, treatment failure may occur despite retention of wild-type XPO1, owing to inadequate intracellular drug concentrations rather than loss of target sensitivity. In addition, ABC transporters substantially influence the systemic pharmacokinetics of SINE compounds by affecting their absorption, distribution and excretion, while also limiting penetration into pharmacological sanctuary sites such as the brain and cerebrospinal fluid (167).

Strategies to overcome this pharmacokinetic resistance include co-administering potent ABC transporter inhibitors and developing nanoparticle-based delivery systems designed to bypass efflux pumps (168). Furthermore, second-generation SINE compounds, such as KPT-8602 (Eltanexor), have been developed to address some of these limitations. Eltanexor shows reduced central nervous system penetration and improved tolerability, allowing more frequent dosing schedules that may sustain higher intracellular drug concentrations and reduce the impact of efflux-mediated resistance (169).

Evidence from high-risk multiple myeloma has shown that XPO1 overexpression itself can contribute to resistance (170). Increased target-protein abundance requires higher drug concentrations to fully occupy Cys528 binding sites, allowing residual oncogenic nuclear export activity to persist despite treatment. Moreover, resistance to SINE compounds appears to be a gradual and complex process involving extensive cellular adaptation. Comparative analyses of parental and SINE-resistant cells have identified substantial alterations in signalling pathways, including changes in the expression of genes associated with inflammation, cell adhesion and apoptosis. These findings suggest a broad transcriptional reprogramming response that enables cancer cells to activate compensatory pathways and circumvent the antitumour effects resulting from SINE-induced nuclear retention of tumour suppressor proteins. The persistence of reduced nuclear accumulation of these proteins, together with sustained alterations in protein expression profiles, further supports adaptive survival mechanisms in resistant cells (171).

Notably, XPO1 overexpression is a common feature of gynaecological malignancies, although XPO1 is also markedly expressed in normal reproductive tissues. A pan-cancer analysis of normal tissues using data from the Genotype-Tissue Expression (GTEx) project demonstrated that elevated XPO1 expression is not restricted to malignant tissues. Expression levels in normal ovarian and uterine tissues were relatively higher than those observed in tissues such as the heart and blood (172). Collectively, these findings indicate that high XPO1 expression is a physiological characteristic of female reproductive organs. However, persistent or further elevated XPO1 expression appears to contribute to tumour progression and chemoresistance in gynaecological malignancies, including ovarian carcinoma.

Pharmacodynamic resistance refers to the ability of tumour cells to tolerate target inhibition by activating compensatory survival mechanisms. Selinexor promotes the nuclear retention of several negative regulators, including Iκα, PTEN and FOXO1/3a, thereby suppressing the NF-κB and PI3K-AKT signalling pathways (173). Nevertheless, SINE-resistant cells have been reported to exhibit markedly elevated basal NF-κB activity. Although Selinexor suppresses NF-κB signalling by retaining Iκα in the nucleus, persistent enhanced basal NF-κB activity suggests adaptive activation of upstream or parallel signalling networks that bypass this XPO1-dependent regulatory checkpoint (174).

In addition, XPO1 inhibition has been shown to induce dose- and time-dependent autophagy in glioblastoma cells. Rather than representing a passive consequence of treatment, this autophagic response functions as a potent cytoprotective mechanism that enables tumour cells to withstand Selinexor-induced stress. Mechanistically, this effect has been linked to nuclear retention of transcription factor EB (TFEB), a recognised XPO1 cargo protein, which activates genes involved in autophagic initiation and maintenance. Notably, both genetic and pharmacological inhibition of autophagy, including chloroquine treatment, markedly enhanced sensitivity to Selinexor, increased apoptosis, and prolonged survival in intracranial mouse models. These findings suggest that targeting treatment-induced autophagy may be a viable strategy to improve the efficacy of SINE compounds (175). This adaptive mechanism may also be relevant to ovarian cancer, in which therapeutic stressors, including cisplatin and SINE treatment, activate ERK signalling and induce autophagy as a survival response (176). However, although TFEB-mediated cytoprotective autophagy has been demonstrated in glioblastoma, its contribution to resistance in gynaecological cancers remains hypothetical and requires further validation.

The tumour microenvironment (TME) contributes to therapeutic resistance by inducing cellular stress responses and promoting immune evasion. In multiple myeloma, the hypoxic bone marrow niche plays a central role in disease progression and resistance to conventional therapies. Notably, Selinexor has demonstrated the ability to overcome this microenvironment-driven resistance. In preclinical models, Selinexor reduced tumour burden and restored sensitivity to bortezomib, with proapoptotic effects being particularly pronounced under hypoxic conditions. These observations indicate that XPO1 inhibition disrupts critical survival pathways supported by the hypoxic TME, supporting the use of Selinexor to restore drug sensitivity in proteasome inhibitor-refractory disease (177).

Beyond its role in adaptation to microenvironmental stress, XPO1 activity has also been implicated in tumour immune evasion. The TME is characterised by the accumulation of regulatory T cells, which suppress effector T-cell function by secreting inhibitory cytokines such as TGF-β and IL-10. At the same time, increased expression of immune checkpoint molecules, particularly PD-L1, promotes T-cell exhaustion and facilitates tumour survival (178). In gynaecological cancer models, XPO1 inhibition has been shown to convert immunosuppressive myeloid-derived suppressor cells into neutrophil-like cells with T-cell-activating properties through nuclear retention of ERK1/2, thereby enhancing antitumour immune responses (179,180).

If elevated XPO1 activity contributes to the establishment of an immune-depleted TME, resistance mechanisms that preserve XPO1 function, including mutation, overexpression or pharmacokinetic drug efflux, may simultaneously maintain an immunosuppressive environment. Consequently, effective strategies to overcome SINE resistance may require integration of nuclear export inhibitors with immunomodulatory therapies, including immune checkpoint blockade, to reverse immune suppression and enhance cytotoxic T-cell activity (181). Supporting this concept, decitabine priming combined with Selinexor significantly reduced tumour burden and ascites formation while enhancing effector T-cell function in ovarian cancer models (182).

High XPO1 expression has also been negatively associated with interferon-γ (IFN-γ) signalling activity (183). IFN-γ exerts complex and context-dependent effects in gynaecological malignancies. In cervical cancer, IFN-γ promotes antitumour immunity by enhancing tumour cell susceptibility to cytotoxic T lymphocyte-mediated killing through upregulation of major histocompatibility complex class I molecules and CD54 expression (184). By contrast, IFN-γ signalling in ovarian cancer may facilitate immune evasion by activating the JAK/STAT1 pathway, increasing expression of PD-L1 and the proto-oncogene BCL3. Furthermore, IFN-γ-induced activation of JAK/STAT1 signalling and proteasomal pathways promotes expression of the non-classical major histocompatibility complex molecule HLA-E, which suppresses natural killer cell-mediated cytotoxicity and is associated with poor clinical outcomes.

XPO1, the principal nuclear export protein, reinforces this resistant phenotype in several malignancies, including ovarian cancer, where its overexpression associates with poor survival and chemoresistance through aberrant nuclear export of tumour suppressor proteins such as p53. Although a direct and universal regulatory relationship between IFN-γ signalling and XPO1 activity has not been established, XPO1 inhibitors such as Selinexor can restore platinum sensitivity in resistant ovarian cancer cells. These findings suggest that IFN-γ-mediated immune escape and XPO1-driven therapeutic resistance represent complementary but mechanistically distinct pathways that collectively enhance ovarian tumour fitness (185).

Selective inhibition of XPO1 using SINE compounds represents an important therapeutic strategy in oncology. However, complex, multifactorial resistance mechanisms constrain the long-term efficacy of this approach. Effectively managing SINE resistance will require a comprehensive strategy that simultaneously addresses genetic, pharmacokinetic, and pharmacodynamic contributors to treatment failure. One promising approach combines SINE compounds with agents that inhibit or counteract compensatory survival pathways activated in response to XPO1 inhibition, restoring therapeutic sensitivity and improving clinical outcomes.