The priority delivery and activation strategies for OSCC-oriented PROTAC development are summarized in Table II. Local mucoadhesive and transmucosal platforms should be prioritized. For OSCC, local mucoadhesive and transmucosal platforms should be considered the most immediately relevant delivery strategies. Compared with fully systemic administration, mucoadhesive patches, bilayer transmucosal devices and intelligent hydrogels can extend residence time at the lesion, counteract salivary clearance and maintain high local drug concentrations while limiting systemic exposure (24,25). This approach is particularly promising for superficial or anatomically accessible lesions on the tongue, floor of mouth, buccal mucosa and gingiva (24). Additionally, directional or backing-layer designs are particularly valuable in the oral cavity, as they can reduce washout and promote drug flux toward the lesion rather than into the saliva (25,28).

The strongest clinical proof-of-principle for localized delivery in oral cancer is not yet demonstrated by a PROTAC, but by the PRV111 transmucosal cisplatin patch (28). In a phase 1/2 study, PRV111 achieved significant local tumor reduction within ~7 days, with high response rates and negligible systemic cisplatin exposure (28). The patch architecture was specifically designed to enhance transmucosal penetration and reduce washout in the oral cavity. Although this does not validate PROTAC efficacy in OSCC, it strongly supports the translational potential of localized transmucosal delivery for oral cancer (24,28). Therefore, PROTACs adapted to similar local-retention platforms may be more clinically relevant to OSCC than strategies focusing solely on systemic administration (19,24,28).

Stimuli-responsive local activation integrated with radiotherapy or light is the second most promising strategy. The second most promising strategy for OSCC is stimuli-responsive local activation (24,29). This approach holds particular promise in oral cancer due to the direct accessibility of numerous lesions to light and the ongoing role of radiotherapy in locoregional treatment (24,29). In the broader PROTAC field, radiotherapy-triggered PROTAC prodrugs have demonstrated X-ray-controlled activation, allowing spatiotemporal restriction of target degradation (30). Similarly, near-infrared-activatable PROTAC nanocages and related smart nano-PROTAC platforms have shown that external local triggers can enhance selectivity and minimize premature systemic activity (29,31).

For oral cancer, this strategy offers a conceptual advantage over constitutively active degraders, as it could restrict protein degradation to the irradiated or illuminated tumor region, thereby limiting systemic and off-tissue degradation (24,29). Moreover, oral lesions are more amenable to controlled local illumination than deeply seated visceral tumors, making photoactivatable or PDT-coupled degrader systems more feasible in this context than in other solid tumors (24,29). However, these systems remain technically complex and should be regarded as high-potential but early-stage approaches, rather than near-clinical solutions (29,31).

Microneedle-assisted locoregional delivery is a highly relevant enabling technology. Microneedle-assisted delivery warrants special consideration in an OSCC-focused review due to its potential to address a key limitation of PROTACs: Inadequate penetration across epithelial and mucosal surfaces (26,32,33). A proof-of-concept study has demonstrated that microneedle patches can deliver PROTACs directly into tumors, validating the feasibility of localized physical delivery for degraders (32). Concurrently, oral mucosal delivery research indicates that microneedles can cross the oral epithelium with minimal pain, while environment-adaptive and mucoadhesive designs are being developed to overcome challenges such as wet adhesion failure, salivary clearance and limited penetration in oral lesions (26,33). However, this strategy must be critically assessed. Microneedle systems still face practical limitations related to drug loading, reproducibility, sterility testing, retention under oral motion and integration into clinical workflows (26,33). Therefore, microneedles should be viewed as an enabling method for localized PROTAC delivery, rather than as a fully mature clinical solution.

Broad systemic nanocarriers and conjugate platforms should be presented as complementary, not primary, strategies. Conventional nanocarriers, exosomes, antibody-based conjugates and other biomolecule-assisted platforms remain scientifically valuable, particularly for metastatic, deeply infiltrative or non-accessible disease (20,27). However, in the context of an OSCC-focused review, these platforms should not dominate the delivery discussion (24,27). A key reason is that passive tumor accumulation via the enhanced permeability and retention (EPR) effect is heterogeneous across human solid tumors and becomes less reliable as tumor architecture and perfusion complexity increase (27). Therefore, claims that nanoparticles will preferentially accumulate in OSCC solely due to EPR should be reconsidered. These platforms become more compelling when combined with oral-cancer-specific ligands, local administration strategies or multi-stimulus activation, rather than being presented as universally superior solutions (20,27).

Resistance, safety and rational combination strategies. For OSCC, combination strategies should be examined within a locoregional clinical framework, rather than simply as generic multi-drug approaches (24,29). Rational combinations may involve PROTACs paired with radiotherapy-triggered activation, PDT-enabled activation for superficial lesions or postoperative local delivery to high-risk mucosal areas (28,30). However, these opportunities should be discussed alongside their limitations, such as overlapping mucosal toxicity, uncertain effects on wound healing, incomplete penetration into deeply infiltrative tumor regions, and limited effectiveness for nodal or distant disease. This is particularly critical in oral cancer, where local control, function preservation and quality of life are intricately linked.

To improve the alignment of target protein ligand selection with the pathogenesis of OSCC, degradable targets should be prioritized based on the strength of oral cancer-specific evidence rather than the mere availability of PROTAC chemistry. It is useful to categorize the evidence into three levels: i) Proteins where degrader activity has been demonstrated in OSCC/HNSCC models; ii) proteins with strong biological validation in OSCC but lacking oral cancer-specific degrader data; and iii) targets primarily supported by extrapolation from other solid tumors. This classification is crucial in oral cancer, where a number of promising degrader targets remain biologically plausible but lack disease-specific validation; for example, c-Myc or CDK/cyclin-axis degraders may be relevant to OSCC biology but still require direct OSCC/HNSCC degrader testing before they can be considered validated oral cancer targets.

Direct PROTAC evidence in oral cancer is currently limited and remains preclinical; however, several relevant HNSCC models provide useful insights. For example, the small-molecule STAT3 degrader (TSM-1) demonstrated selective STAT3 degradation and robust antitumor activity in STAT3-dependent HNSCC models, including patient-derived systems (34). Similarly, Fos-related antigen 1 (FOSL1)-targeting PROTAC probes effectively degraded FOSL1 and suppressed cancer stem cell phenotypes in HNSCC, with enhanced potency compared with the parent ligand (35). Additionally, radiotherapy-activated PROTAC prodrug-integrated nanosensitizers have shown tumor regression in HNSCC models, illustrating that targeted degradation can be integrated into clinically relevant treatment settings in head and neck cancer (36). BET-family degrader activity, particularly targeting BRD4, has also been explored in cisplatin-resistant HNSCC, supporting the concept that targeted degradation can address therapy resistance rather than simply baseline tumor growth (37).

Among biologically supported candidate targets in OSCC, EGFR remains highly relevant due to its frequent overexpression and association with poor prognosis in oral and oropharyngeal squamous cell carcinoma (38,39). While oral cancer-specific EGFR degraders have not been clinically validated, the development of orally active EGFR-PROTAC candidates in other epithelial tumors supports further translational investigation. c-Myc is also biologically relevant in OSCC, but current degrader evidence mainly comes from non-oral tumor models, making it more appropriate to consider c-Myc a plausible rather than validated oral cancer degrader target at this stage (40,41).

The cell-cycle axis is more directly supported in OSCC than is apparent from generalized PROTAC discussions. Cyclin D1 overexpression is consistently linked to aggressive clinicopathological features and a poor prognosis in OSCC, including lymph node metastasis and inferior survival outcomes (42–44). Consequently, the discussion of cyclin-directed or CDK/cyclin-axis degraders is biologically justified in OSCC, even though current degrader data predominantly come from non-OSCC models. The same rationale applies to metabolic vulnerabilities. Hexokinase 2 (HK2) has been associated with glycolytic reprogramming, invasion and metastasis in OSCC and tongue squamous cell carcinoma, indicating that HK2-targeted degradation may address a biologically substantiated dependency rather than a generic cancer pathway (45–47).

Epigenetic regulators are among the most compelling candidates for targeted degradation in oral cancer, supported by both oral cancer biology and the tractability of degrader approaches. BRD4 is upregulated in primary HNSCC and has been implicated in OSCC invasion and metastasis, while p300 (encoded by EP300)-related signaling is also associated with OSCC progression (48–51). Consequently, BET/BRD4 and CBP/p300 degraders represent more convincing candidates for OSCC than several targets currently discussed through cross-cancer analogy. Notably, a recent multi-omics analysis suggests that OSCC is not a molecularly uniform disease and that precision stratification based on biomarkers, such as EGFR-associated or immune-related states, may provide more informative guidance than a one-size-fits-all development strategy (52). The strongest priorities for oral cancer, therefore, are targets that meet two criteria: Biological relevance in OSCC/HNSCC and practical tractability for TPD. By contrast, targets without clear enrichment or validation in oral carcinogenesis should be framed explicitly as speculative extensions rather than core priorities for OSCC.

Clinical progress in TPD has established proof of principle in oncology, but OSCC/HNSCC-specific clinical validation of PROTACs has not yet been established. Available clinical evidence has not yet demonstrated OSCC/HNSCC-specific outcomes such as objective response, progression-free survival or survival benefit; therefore, current evidence in this disease context should be interpreted as HNSCC-supported preclinical evidence or platform-level clinical extrapolation rather than oral cancer-specific proof (7,16,34,36,37). Among current clinical-stage degrader programs, breast cancer provides one of the clearest examples of clinical validation, where vepdegestrant demonstrated phase 3 efficacy in the VERITAC-2 program. A more pronounced benefit was observed in patients with estrogen receptor 1 (ESR1)-mutated, estrogen receptor (ER)-positive, HER2-negative advanced breast cancer (53,54). In this ESR1-mutated population, vepdegestrant improved median progression-free survival time compared with fulvestrant (5.0 vs. 2.1 months; hazard ratio, 0.58), whereas the benefit in the overall population was more modest, suggesting biomarker-defined rather than universal efficacy (54). In prostate cancer, bavdegalutamide and HP518 have shown promising early clinical activity in phase 1/2 and phase 1 studies, respectively (55,56). Bavdegalutamide achieved a median radiographic progression-free survival time of 8.2 months in tumors with androgen receptor (AR) ligand-binding-domain mutations excluding L702H and 11.1 months in the AR 878/875 subgroup without co-occurring L702H; HP518 phase 1 data included two partial responses and three prostate-specific antigen reduction of ≥50% (PSA50) responses (55,56). However, these programs highlight an important lesson for the field: Clinical benefit may be biomarker-defined and pharmacologically constrained, rather than uniformly observed across all patients (54,55). Collectively, these findings validate the PROTAC platform in humans, but they do not establish efficacy in OSCC/HNSCC (16,54,56).

In OSCC/HNSCC, available direct evidence remains mainly preclinical. STAT3 degradation by TSM-1 has shown antitumor activity in STAT3-dependent HNSCC models, including patient-derived systems (34). Radiotherapy-activated PROTAC prodrug-integrated nanosensitizers and BET degraders have also shown activity in HNSCC models or cisplatin-resistant HNSCC cells (36,37). These studies support the biological plausibility of targeted degradation in head and neck cancer, but they do not yet provide patient-level clinical endpoints. Thus, OSCC/HNSCC-related evidence should be viewed as a translational rationale for further development rather than as clinical validation.

For oral cancer, the primary translational gap is no longer whether PROTACs can work clinically in principle, but whether the correct target, route of delivery and exposure profile can be achieved in a disease characterized by distinct locoregional behavior and mucosal biology (7,16). In this context, it is more defensible to prioritize proteins already supported by OSCC/HNSCC biology or direct head and neck degrader studies, while explicitly labeling other applications as hypothesis-generating rather than validated.

Several practical barriers remain particularly relevant for translating PROTACs to oral cancer. First, their relatively high molecular weight and complex physicochemical properties complicate membrane permeability, formulation and systemic oral exposure (19,20,57). Second, selectivity is limited by the small number of commonly recruited E3 ligases, primarily CRBN and VHL, which may restrict tissue specificity (7,18). Third, on-target/off-tumor toxicity and adaptive resistance remain significant concerns, especially when degraded proteins play key physiological roles in normal tissues or when tumors can rewire compensatory signaling and proteostasis pathways (16,18). Fourth, while a number of advanced delivery systems are conceptually elegant, they also introduce manufacturing, scalability and regulatory challenges. From an oral cancer perspective, local or locoregional delivery is appealing, though this strategy still requires dedicated validation in oral tumor models and clinically realistic settings (20,57).

In summary, current clinical evidence should be viewed as platform-level validation rather than oral cancer-specific proof (16,54,56). For OSCC, the next step is not merely adopting successful degraders from other tumor types, but developing biomarker-guided, disease-contextualized PROTAC strategies that reflect the unique molecular dependencies and therapeutic constraints of oral cancer itself (7,20,57).

Future directions for oral cancer treatment. The future development of PROTAC-based strategies for OSCC should shift from generalized enthusiasm for TPD to a more focused, biomarker-guided, disease-contextualized approach. The first priority is target nomination based on oral cancer-specific molecular stratification, rather than indiscriminately borrowing degrader targets from other malignancies (52,58). Recent multi-omics studies in OSCC have revealed that distinct biomarker-defined subgroups, including EGFR-associated and immune-inflamed states, exhibit varying recurrence risks and therapeutic vulnerabilities. This highlights the necessity for degrader development programs that align with the biological context of oral cancer, rather than relying solely on generic pathway prevalence (52,58). These findings support a strategy that incorporates both tumor-intrinsic oncogenic drivers and microenvironment-linked dependencies (52,58).

The second priority is the intentional development of local and locoregional PROTAC delivery strategies tailored to the oral cavity (24–26). In OSCC, the translational question is not simply whether a degrader can be systemically administered, but whether it can be retained, activated and distributed effectively within a wet, mobile and barrier-rich mucosal environment. For this reason, local transmucosal platforms, stimuli-responsive systems integrated with radiotherapy or light, and microneedle-assisted delivery should be prioritized as primary approaches, rather than supplementary strategies for oral cancer translation (26,28). Additionally, future medicinal chemistry efforts should more explicitly consider compatibility with local delivery, focusing on parameters such as directional release, wet adhesion and spatially restricted activation, instead of solely optimizing conventional systemic drug-likeness (19,20).

A third priority is the use of clinically relevant preclinical platforms that can support biomarker selection, drug screening and resistance analysis (59–61). OSCC and HNSCC organoid systems provide a more accurate framework for modeling epithelial-stromal interactions, treatment responses and intra-tumoral heterogeneity than conventional 2D cell lines alone (59,61). In HNSCC, patient-derived tumor organoid workflows have demonstrated practical feasibility for treatment decision-making in a notable proportion of patients, although procedural and logistical challenges remain (60). Reviews of OSCC preclinical platforms emphasize that patient-derived cell lines, xenografts and organoids should be integrated, as each model captures different aspects of tumor biology and therapeutic vulnerability (62,63).

Finally, the clinical translation of PROTACs in OSCC will likely require small, biomarker-enriched, anatomy-aware early-phase studies, rather than broad efficacy trials (52,58,60). Initial trials may be best designed around accessible lesions, clearly defined target-expression profiles and delivery platforms that allow pharmacodynamic sampling of degraded proteins within local tissue (28,60). This approach would facilitate PROTAC development in oral cancer with stronger mechanistic validation and more precise patient selection than is currently possible by broadly extrapolating from other solid tumors. In this context, the next step for PROTACs in OSCC is not simply further chemistry, but enhanced biological prioritization, refined local delivery engineering and improved translational models (19,20). Fig. 1 summarizes this proposed discovery-to-clinic pathway by linking OSCC biological stratification, target prioritization, local or locoregional delivery selection, pharmacodynamic sampling and early-phase clinical validation.

The present review has several limitations. First, while TPD has gained increasing clinical validation as a therapeutic platform, direct evidence supporting PROTAC application in OSCC remains limited and predominantly preclinical. Consequently, some of the discussion relies on data from HNSCC or extrapolation from other solid tumors, such as breast and prostate cancer, which may not fully capture the unique molecular dependencies, tumor microenvironment and treatment context of OSCC. Second, the present study is a narrative review informed by a structured literature search rather than a formal systematic review or meta-analysis. As a result, study selection bias and heterogeneity in the quality of included evidence cannot be entirely excluded. Third, the degrader literature is highly heterogeneous in terms of target selection, chemical scaffolds, E3 ligase usage, model systems, delivery platforms and pharmacodynamic endpoints, limiting direct cross-study comparison. Fourth, some clinically relevant information in this field is still emerging from conference abstracts, early-phase reports or rapidly evolving trial updates, which may affect the stability of evidence interpretation. Finally, OSCC itself is biologically heterogeneous, with variations in anatomical subsite, stromal architecture, local microbial and salivary environment, and treatment setting. These disease-specific factors remain insufficiently addressed in most current degrader studies. These limitations highlight that the present review should be regarded as an OSCC-centered translational framework rather than definitive clinical guidance.