Cervical cancer is the second most common malignant tumor affecting women’s health globally, with over 660,000 new cases and more than 340,000 deaths reported annually worldwide (Bray et al., 2024). The primary treatment for cervical cancer patients typically involves surgery, chemoradiotherapy, or a combination of these modalities, with the choice depending on the stage of the cancer. In recent years, the incorporation of pembrolizumab, an anti-programmed death 1 (PD-1) monoclonal antibody (mAb), and bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) mAb, has significantly transformed the therapeutic paradigm for cervical cancer.

The phase III GOG-240 trial (NCT00803062) showed that adding bevacizumab to chemotherapy significantly improved median overall survival (OS) by 3.7 months (17.0 months vs. 13.3 months) in patients with recurrent, persistent, or metastatic cervical cancer (Tewari et al., 2014). Combination chemotherapy plus bevacizumab has become the standard first-line (1L) treatment for patients with advanced cervical cancer. Based on the phase III KEYNOTE-826 trial (NCT03635567) results, pembrolizumab in combination with chemotherapy (with or without bevacizumab) is the preferred 1L treatment for programmed death-ligand 1 (PD-L1)-positive recurrent and metastatic cervical cancer (r/mCC) (Colombo et al., 2021). Treatment options after 1L progression remain limited, with second-line (2L) and subsequent chemotherapy regimens typically showing low response rates and median progression-free survival (PFS) of 3–6 months (Porras et al., 2018; Boussios et al., 2016). Patients with metastatic, recurrent, or persistent cervical cancer face poor prognosis, demonstrating a 5-year survival rate of less than 20% (Giudice et al., 2021). There remains a substantial unmet need for novel treatment strategies that are both effective and well-tolerated among the population with r/mCC, who continue to face poor prognoses and limited therapeutic options.

The rapid advancement of targeted therapy has brought renewed hope to these patients. Targeted therapy relies on the overexpression of specific antigens on the surface of tumor cells, which are rarely or not expressed in normal cells. In-depth investigation of tumor-associated antigens (TAAs) provides crucial insights into the pathological mechanisms of epithelial barrier dysfunction and facilitates the development of precision therapies, demonstrating significant translational value particularly in the field of targeted cancer treatment. A variety of targeted therapeutics have been developed to address different TAAs, including mAbs, bispecific antibodies, small molecule inhibitors, antibody-drug conjugates (ADCs), nanoparticles, and chimeric antigen receptor T cells. Among these, ADCs have emerged as a revolutionary targeted treatment approach for both hematologic malignancies and various refractory and advanced solid tumors.

ADC is a targeted biologic agent that links a cytotoxic drug (known as the payload) to a mAb via a chemical linker (Chau et al., 2019). By utilizing the mAb as a carrier, ADCs effectively deliver small-molecule cytotoxic drugs to target tumor cells (Tarantino et al., 2022). This approach preserves the antitumor properties of the cytotoxic payload while reducing its off-target effects, thereby significantly improving the benefit-risk ratio of anticancer therapy. The ability of ADCs to selectively target and eradicate cancer cells has markedly advanced the treatment of difficult-to-treat malignancies. Preclinical and clinical research on ADCs for the treatment of cervical cancer is being actively conducted worldwide. These ADCs offer additional therapeutic options for patients with advanced cervical cancer, particularly for those who have progressed after multiple lines of therapy, and hold the potential to improve clinical outcomes. This article reviews potential ADC targets in cervical cancer and their mechanisms of action in tumor biology, summarizes the latest clinical trial results of representative ADCs (as shown in Table 1) in cervical cancer, and provides an outlook on the future prospects and directions of ADC applications.

TF, also known as coagulation factor III, thromboplastin, F3, or CD142, is a transmembrane glycoprotein is encoded by the F3 gene located on chromosome 1p21.3 in humans, spanning approximately 12.4 kb in length (Platform MCPP and monoclonal Abs A-T, 2025). Under physiological conditions, TF binds the coagulation serine protease factor VII/VIIa (FVII/VIIa) to initiate the extrinsic coagulation pathway for hemostasis (Mackman, 2004). TF shows basal expression in vascular cells (e.g., smooth muscle cells, fibroblasts, and pericytes) but is aberrantly overexpressed in cervical cancer and other solid tumors (Leppert and Eisenreich, 2015). TF overexpression is associated with increased tumor aggressiveness and poor prognosis, and plays a role in tumor progression, invasion, metastasis, and angiogenesis.

The most critical component of TF’s non-hemostatic functions is the direct or indirect cellular signaling induced by the TF-FVIIa complex. On the surface of tumor cells, the TF-FVIIa complex generates pro-angiogenic factors, such as VEGF, through protease-activated receptor 2 (PAR2)-mediated intracellular signaling pathways, thereby stimulating tumor angiogenesis (Kocatürk and Versteeg, 2013)^, (Schaffner and Ruf, 2009). Additionally, it activates the janus kinase 2 and signal transducers and activators of transcripition 5 (JAK2-STAT5) pathway to produce the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2), which inhibits cancer cell apoptosis (Fang et al., 2008). PAR2 stabilizes β-catenin, leading to tumor cell invasion. PAR2 also activates the mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) 1/2 pathways, while upregulating β-arrestin. This phosphorylates cofilin, triggering actin filament polymerization at the leading edges of invading tumor cells, thereby enhancing their invasive and metastatic potential (Ahmadi et al., 2023). TF can stimulate tumor formation by regulating immunity and promoting inflammation (Hisada and Mackman, 2019).

The expression of TF by tumors may promote metastasis by inducing fibrin encapsulation of tumor cells, thereby trapping them within microvessels. Additionally, intravascular thrombosis may activate endothelial cells and induce the expression of adhesion molecules, facilitating tumor cell extravasation into extravascular spaces (Kasthuri et al., 2009). Moreover, TF can induce the secretion of matrix metalloproteinases, which degrade the surrounding extracellular matrix, thereby facilitating tumor cell invasion into adjacent tissues and promoting distant metastasis (Eble and Niland, 2019). TF is highly expressed in up to 95% of cervical cancer (Zhao et al., 2018), and has been identified as a promising therapeutic target for cervical cancer.

HER2 is a transmembrane protein encoded by the erbB2 gene located on chromosome 17q12 (Popescu et al., 1989). As a member of the HER/erbB family, it shares high homology with HER1 (epidermal growth factor receptor, EGFR), HER3, and HER4. These receptors regulate key signaling pathways for cell growth, differentiation, and survival (Popescu et al., 1989; Rubin and Yarden, 2001). HER2 typically responds to extracellular signals by forming heterodimers with other erbB family members, thereby initiating intracellular signaling networks (Arkhipov et al., 2013). Heterodimers containing HER2 generate significantly stronger intracellular signals than other HER family pairings. Under normal physiological conditions, HER2 exhibits minimal surface expression in cells, resulting in fewer heterodimers and consequently weaker, more tightly regulated growth signals. However, HER2 gene amplification or protein overexpression leads to dramatically increased HER2 surface density. This overexpression promotes excessive homodimer (HER2/HER2) or heterodimer (e.g., HER2/HER3, HER2/HER4) formation. Notably, these dimers exhibit ligand-independent activation and demonstrate enhanced signaling potency, causing sustained activation of downstream pathways, particularly phosphatidylinositol-3 kinase/AKT serine/threonine tinase (PI3K/AKT) and MAPK pathway (Rubin and Yarden, 2001). This aberrant signaling drives uncontrolled cellular processes including proliferation, survival, invasion, and anti-apoptotic activity.

Additionally, abnormal HER2 signaling can increase the invasiveness and metastatic potential of tumor cells and activate multiple anti-apoptotic pathways, rendering tumor cells resistant to treatment (Spector and Blackwell, 2009; Citri and Yarden, 2006; Gutierrez and Schiff, 2011). Given its frequent overexpression in human malignancies contrasted with low expression in normal tissues, HER2 has emerged as an attractive therapeutic target for solid tumors. A systematic review and meta-analysis estimated the overall prevalence of HER2 overexpression in cervical cancer to be 5.7% and HER2 amplification to be 1.2% (Itkin et al., 2021). The NCCN Guidelines Panel recommends HER2 immunohistochemistry (IHC) testing for patients with advanced and r/mCC (Category 2A) (Abu-Rustum et al., 2023). Several HER2-targeting ADCs with novel payloads have demonstrated efficacy in cervical cancer.

Trop-2, also known as tumor-associated calcium signal transducer 2, epithelial glycoprotein-1, gastrointestinal antigen 733–1, and membrane component 1 surface marker 1, is a type I transmembrane glycoprotein and transmembrane calcium signal transducer encoded by the 1p32.1 locus on the short arm of chromosome 1 (Lipinski et al., 1981; Toumi and Mathe, 2023). The protein is frequently overexpressed in various epithelial malignancies (e.g., BC, colorectal carcinoma) while being virtually undetectable in normal adult tissues (Lipinski et al., 1981; Goldenberg et al., 2018). Studies have confirmed that Trop-2 plays a significant role in cell proliferation, apoptosis, cell adhesion, epithelial-mesenchymal transition, as well as tumorigenesis and progression. Trop-2 is typically expressed in cervical cancer, particularly in squamous cell carcinoma, but is not expressed in normal cervical tissues (Zeybek et al., 2020; Chiba et al., 2024; Varughese et al., 2011). Its overexpression in cervical cancer tissues is associated with International Federation of Gynecology and Obstetrics staging, histological grade, lymph node metastasis, depth of stromal invasion, and high expression of Ki-67 (Liu et al., 2013). Cervical cancer patients with positive Trop-2 expression exhibit poorer OS and PFS (Liu et al., 2013).

The biological role of Trop-2 in cervical cancer is still under investigation. High levels of Trop-2 protien can enhance the activity of the transcription factor activator protein 1 (AP-1) through the MAPK/ERK signaling pathway (Cubas et al., 2010; Lin et al., 2012). AP-1 promotes angiogenesis through VEGF, drives cell proliferation via cyclins and cyclin-dependent kinases (CDKs), induces apoptosis through Bcl-2 or Fas ligand, and mediates cell invasion and metastasis through matrix metalloproteinases (Shvartsur and Bonavida, 2015). Liu et al. discovered that in human cervical cancer cells, the expression of Bcl-2 increased, while the expression of the pro-apoptotic protein bax decreased (Liu et al., 2013). Trop-2 inhibits apoptosis by directly upregulating Bcl-2 expression and suppressing bax activation (Liu et al., 2013; Chen et al., 2012). Trop-2 stimulates the expression of cell cycle regulators such as cyclin D1, cyclin E, CDK2, and CDK4 by modulating the ERK1/2 pathway, thereby promoting the G1-S and G2-M transitions, accelerating cell cycle progression, and ultimately enhancing cell proliferation (Liu et al., 2013; Cubas et al., 2010).

Trop-2 inhibits cell adhesion to fibronectin by increasing the binding of β1 integrin to the adapter molecule receptor for activated C kinase one and activating the activity of tyrosine kinase c-Src and focal adhesion kinase, leading to increased invasiveness of cancer cells (Trerotola et al., 2012). Overexpressed Trop-2 forms a complex with insulin-like growth factor 1, which inhibits the insulin-like growth factor 1 receptor signaling pathway. This inhibition suppresses the activation of β-catenin/Slug gene expression, thereby mediating the proliferation and migration of tumor cells (Pavšič et al., 2015). Trop-2 also can restrict the expression of the calcium-dependent cell adhesion molecule E-cadherin, and induces the loss of intercellular adhesion (Liu et al., 2013; Tang et al., 2011). Consequently, these effects promote the epithelial-mesenchymal transition (EMT). In solid tumors, the transition of epithelial cells to mesenchymal cells is a crucial early step in tumor invasion and metastasis (Slabáková et al., 2011). Trop-2 has emerged as a promising new molecular target for ADC due to its differential expression in normal versus tumor tissues and its internalization activity.

Mesothelin is a differentiation antigen expressed on normal mesothelial cells and is overexpressed in several human malignancies, including mesothelioma, ovarian adenocarcinoma, and pancreatic adenocarcinoma (Hassan et al., 2004). Mesothelin may be involved in tumor initiation, progression, invasion, and metastasis through multiple signaling pathways. Mesothelin binds to mucin16/carbohydrate antigen 125 (Kaneko et al., 2009), downregulates Dickkopf-1 (an inhibitor of the Wnt signaling pathway) through the serum and glucocorticoid-regulated kinase 3 (SGK3)/forkhead box O3 (FoxO3) signaling pathway, and activates the Wnt/β-catenin axis, thereby promoting cancer cell metastasis (Huo et al., 2021). The overexpression of mesothelin activates the PI3K/AKT, ERK1/2, and c-Jun N-terminal kinase (JNK) signaling pathways (Wang et al., 2012). The downstream effects of AKT and ERK1/2 signaling include the inhibition of pro-apoptotic proteins such as Bim, Bad, and Bax, as well as the stimulation of anti-apoptotic proteins like Bcl-xl and Bcl-2, thereby suppressing cellular apoptosis (Tang et al., 2013). The PI3K/AKT, ERK1/2, and JNK pathways can also enhance the expression of matrix metalloprotease 7, thereby promoting cell migration and invasion (Chang et al., 2012). The matrix metalloprotease 7 pathway can be triggered through the SGK3/FoxO3 and p38 pathways as well (Chen et al., 2013). Additionally, the overexpression of mesothelin leads to the activation of the p38, NF-κB and signal transducers and activators of transcripition 3 (STAT3) signaling pathways. The downstream effects of NF-κB include increasing the production of IL-6 and enhancing tumor cell proliferation and survival through auto/paracrine IL-6/sIL-6R trans-signaling (Bharadwaj et al., 2011). Constitutive activation of STAT3 results in increased expression of cyclin E and the formation of the cyclin E/CDK2 complex, promoting the G1-S transition (Faust et al., 2022).

Researches has found that mesothelin is highly expressed in cervical cancer patients, particularly in those with non-squamous cell carcinoma (Jöhrens et al., 2019; He et al., 2019; Takamizawa et al., 2022). High mesothelin expression was associated with poor OS in patients with common histological cervical cancer types (Takamizawa et al., 2022). Given the limited expression of mesothelin in normal tissues, targeting it for the treatment of cervical cancer is a viable strategy. Although clinical trials of mesothelin-targeting agents have primarily focused on pleural mesothelioma, ovarian cancer, and pancreatic cancer, preliminary efficacy has been observed with certain mesothelin-targeting ADCs in cervical cancer patients. This suggests mesothelin-targeting ADCs as promising additional therapeutic strategies for cervical cancer.

Nectin-4 is a Ca²⁺-independent, type I transmembrane, immunoglobulin-like cell adhesion molecule that exhibits restricted physiological expression primarily in embryonic and placental tissues, but is frequently overexpressed in multiple human malignancies (Rikitake et al., 2012). It is involved in various molecular pathways related to tumor cell adhesion, proliferation, migration, and angiogenesis, making it a novel biomarker and therapeutic target for cancer. Nectin-4 exists in both soluble and membrane-bound forms. Under hypoxic conditions, a disintegrin and metalloproteinase can cleave the extracellular domain of this membrane protein from the cell surface, releasing soluble Nectin-4 (Buchanan et al., 2017).

Nectin-4 participates in several critical processes in tumors through the key signaling pathway of PI3K/AKT. The interaction between soluble Nectin-4 and integrin β4 on endothelial cells can regulate the transcriptional activity of Src, PI3K, AKT, and endothelial NO synthase, inducing the formation of NO mediated by the PI3K/AKT signaling pathway, thereby promoting tumor angiogenesis (Zhang et al., 2019; Siddharth et al., 2018). In BC, Nectin-4 and HER2 engage in cis-interactions, activating the PI3K/AKT signaling pathway to enhance DNA synthesis. Soluble Nectin-4 further promotes inositol polyphosphate 4-phosphatase type II-dependent lysosomal degradation via the PI3K/AKT axis, which activates the Wnt/β-catenin signaling pathway, driving the proliferation and metastasis of BC cells (Kedashiro et al., 2019; Siddharth et al., 2017; Rodgers et al., 2023). Additionally, in osteosarcoma, Nectin-4 directly downregulates the microRNA miR-520c-3p, activating the PI3K/AKT/NF-κB pathway and promoting tumor progression and metastasis (Liu et al., 2022). The upregulation of Nectin-4 can also activate the Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling pathway through the PI3K/AKT axis. Activated Rac1 stimulates p21-activated kinases and JNK, which initiate cytoskeletal reorganization and regulate cell adhesion, migration, and proliferation (Zhang et al., 2016).

In addition to the PI3K/AKT pathway, Nectin-4 is also involved in the transduction of other signaling pathways. The extracellular domain of Nectin-4 also interacts in cis with the prolactin receptor, which is essential for mammary follicle development, activating the JAK2–STAT5a signaling pathway, thereby regulating the growth of tumor cells (Maruoka et al., 2017; Tan and Nevalainen, 2008). Nectin-4 regulates intercellular adhesion, remodels the actin cytoskeleton, triggers EMT, enhances the driving force for tumor cell pseudopodia extension, and ultimately leads to tumor development and metastasis (Samanta and Almo, 2015).

Nectin-4’s involvement in cervical cancer pathogenesis is poorly characterized, with sparse data on its expression dynamicsHalle et al. performed IHC analysis of Nectin-4 membrane expression in tumor specimens from 525 cervical cancer patients, identifying high expression levels in 4% of cases (Halle et al., 2024). In the cervical cancer expansion cohort of a clinical trial for a novel Nectin-4-targeting ADC, the detection rate of Nectin-4 expression was 89.67%, and the detection rate of Nectin-4 tumor cell staining intensity of 3+ was 67.82% (Zhai et al., 2024). Emerging evidence suggests that Nectin-4 may activate double-strand DNA repair pathways in cervical cancer stem cells, thereby promoting malignant progression. Supporting this mechanism, Nayak et al. demonstrated that quinacrine nanoparticles-functioning as Nectin-4 inhibitors-effectively suppress both cellular proliferation and DNA damage response in cervical cancer stem cells (Nayak et al., 2019). Nectin-4 could serve as an effective target for cervical cancer, and Nectin-4-targeting ADCs have already demonstrated promising efficacy in cervical cancer patients.

In summary, this article reviews potential targets for ADCs in cervical cancer and elucidates their mechanisms of action in tumor biology. By summarizing the latest clinical trial results of representative ADCs in cervical cancer, we highlight their potential to transform the treatment landscape for patients with recurrent or metastatic disease. Several ADCs, including TV, T-DXd, have already demonstrated significant therapeutic activity in patients with advanced cervical cancer.

While this review comprehensively analyzed the clinical efficacy of ADCs, it is important to note that detailed pharmacokinetic (e.g., clearance rates, volume of distribution) and pharmacodynamic (e.g., target engagement biomarkers) data from the included trials were not publicly available. This gap limits our ability to fully correlate drug exposure with therapeutic outcomes or adverse events. Future trials should prioritize reporting these parameters to facilitate mechanistic understanding of ADCs in cervical cancer.

Future research should focus on identifying novel TAAs and optimizing ADC design through payload diversification and antibody engineering to enhance both efficacy and safety. It is imperative to discover broad-spectrum biomarkers based on ADC mechanisms or pharmacodynamic effects, enabling biomarker-guided patient stratification for precision medicine. Additionally, exploring ADC-based combination therapies may further improve clinical outcomes while mitigating drug resistance. A comprehensive understanding of the biological roles of TAAs in tumor angiogenesis, host immune responses, and multiple cellular signaling pathways will provide critical insights for developing combination therapeutic strategies. Given Trop-2’s regulatory role in cervical cancer progression and host immune responses, clinical trials have been initiated to evaluate the efficacy and safety of combining Trop-2-directed ADCs with ICIs. The synergistic effect of mesothelin and mucin16 in malignant peritoneal metastasis suggests that developing bispecific ADCs may represent a promising strategy to enhance therapeutic efficacy. Furthermore, future research should explore combination therapies pairing ADCs with molecularly targeted agents to simultaneously inhibit multiple signaling pathways. For instance, combining Trop-2-directed ADCs with ERK phosphorylation inhibitors or Nectin-4-targeting ADCs with AKT inhibitors may yield more effective antitumor treatment strategies.

ADCs retain tremendous untapped potential in cervical cancer treatment. As this field continues to advance, ADCs are poised to play an increasingly pivotal role in therapeutic strategies, offering renewed hope for improving survival rates and clinical outcomes for patients worldwide.