Cervical cancer is one of the most common malignancies affecting women worldwide, with significant morbidity and mortality, particularly in low- and middle-income countries (LMIC). As per the GLOBOCAN 2020, cervical cancer is the most common gynaecological cancer and is ranked 8th most common cancer with an annual incidence of 0.6 million [1]. Persistent infection by high-risk types of human papillomavirus (HPV), primarily HPV16 and HPV18 has been linked to the pathogenesis of cervical cancer [2]. Although widespread HPV vaccination programs have dramatically reduced the incidence of cervical cancer in most developed countries with high vaccine coverage, it still remains a significant global problem in LMIC.

Traditionally, the management of cervical cancer has relied on a combination of surgery, radiation therapy, and chemotherapy, depending on the stage of the disease. While these conventional therapies can be effective, particularly in early-stage cancers, they often fail in advanced or recurrent cases. The prognosis for metastatic or recurrent cervical cancer remains poor, highlighting the need for new therapeutic strategies. With conventional chemotherapy, the response rate is around 30% with a median survival of 7 months [3].

In recent years, immunotherapy has emerged as a promising approach in the treatment of various cancers, including cervical cancer. Immunotherapy leverages the body’s immune system to recognize and eliminate tumour cells. Immune checkpoint inhibitors (ICI) have shown efficacy in cervical cancer by targeting immune checkpoints which tumours exploit to evade immune detection. These therapies have demonstrated durable responses in other malignancies in patients with advanced or recurrent cervical cancer, where few options previously existed and even have been recommended in first line settings.

This review will explore the role of immunotherapy in the treatment of cervical cancer, examining current evidence, mechanisms of action, and future directions. As the field evolves, immunotherapy could potentially transform the landscape of cervical cancer treatment, offering hope to patients with limited treatment options.

Cervical cancer is strongly associated with persistent infection by high-risk HPV strains, particularly HPV16 and HPV18. These viruses induce oncogenic changes by expressing E6 and E7 oncoproteins, which disrupt tumor suppressor pathways and promote immune evasion [4]. E6 binds to and promotes the degradation of the tumor suppressor p53 gene, impairing cell cycle arrest and apoptosis. Simultaneously, E7 binds to the retinoblastoma protein (Rb), releasing E2F transcription factors, which drive uncontrolled cell cycle progression. This dual inactivation of p53 and Rb leads to genomic instability, unchecked cell proliferation, and resistance to apoptosis, ultimately resulting in malignant transformation. Given the immunogenic nature of HPV-related antigens, cervical cancer presents a favourable target for immunotherapeutic approaches, including ICI, therapeutic vaccines, and adoptive cell therapy (Figures 1 and 2).

During pathogenesis, HPV integrates into the host genome, where primarily the oncogenic E6 and E7 genes are retained and expressed, while other HPV genes are lost or remain inactive. This makes neutralizing antibodies from prophylactic vaccines ineffective against these infected cells. To address this, therapeutic HPV vaccines are being developed to clear HPV infections and HPV-associated lesions. These vaccines promote T cell-mediated immunity by targeting early HPV antigens consistently expressed in infected and cancerous cells, with E6 and E7 as primary targets.

Live vector-based vaccines utilize bacterial or viral vectors, to stimulate robust cellular and humoral immune responses, often achievable with a single dose. For HPV, bacterial vectors like Listeria monocytogenes have shown promise by stimulating the activation of both helper and cytotoxic T cells against E6/E7, with the ADXS Listeria-based vaccine currently in phase 2 trials [42]. Viral vectors, including adenoviruses and modified vaccinia viruses, can also express HPV antigens in infected cells, engaging the immune system without integrating into the host DNA with some trials showing encouraging immune responses in early-stage cervical and vaginal cancers [43–45]. However, these vaccines must be used with caution, particularly for immunocompromised patients, and pre-existing immunity against the vector can limit efficacy, potentially hindering repeat doses with the same vector type.

DNA vaccines are advantageous for HPV immunotherapy due to their safety, stability, and ability to prompt repeated vaccinations without neutralizing antibodies. While DNA vaccines can stimulate both humoral and cellular immunity, they often need adjuvants or delivery enhancements to boost immunogenicity. For example, intramuscular or intradermal injection introduces DNA to host cells, producing antigens that stimulate immune responses. Clinical trials have explored DNA vaccines like pNGVL4a-CRT-E7, which achieved lesion regression in some patients, and GX-188, which showed viral clearance and enhanced T-cell responses in CIN III cases [46, 47]. Electroporation—a DNA delivery technique—has been used to improve transfection efficiency by temporarily permeabilizing cell membranes, promoting antigen uptake and APC recruitment [48]. Other methods, like gene gun and microencapsulation, are also in development to enhance DNA vaccine efficacy [49]. The REVEAL 1 trial (NCT03185013) recently reported that significant HSIL histopathological regression with HPV16/18 virologic clearance at 36 weeks was achieved in 23.7% vs. 11.3% in the placebo group [50]. Another vaccine, INO-3112, targets HPV16/18 E6 and E7 antigens and includes IL-12. Clinical trials have demonstrated its safety and immune response enhancement as an adjunct to chemoradiation in cervical cancer [51].

Peptide-based vaccines are stable, safe, and easy to produce, though they often require adjuvants due to low immunogenicity [52]. However, they are MHC-restricted, and HPV peptides must be selected for MHC binding and CTL induction. Short peptides are prone to immune tolerance and limited CD4⁺ activation, while long peptides promote robust CTL responses after processing [53]. In clinical trials, long peptide vaccines targeting HPV16 E6 and E7, paired with adjuvants, enhanced IFN-γ T cell responses in cervical cancer patients. Enhancements like the 4-1BB ligand and bryostatin-I improve DC activation and T cell response [54].

Protein vaccines offer a broader MHC response range, allowing APCs to process and present all potential epitopes, making them beneficial for antibody production, though adjuvants are needed to enhance immunogenicity [49]. Clinical trials show promising responses with protein vaccines like SGN-00101 (HPV16 E7-HSP65), which demonstrated clinical response in 78% of CIN III patients, and TA-CIN, which generated HPV16-specific antibodies and T-cell responses in early clinical trials [55, 56]. Combined with the immune modulator imiquimod, TA-CIN showed a 63% remission in patients with VIN II/III, significantly increasing T-cell infiltration in treated lesions [57].

DCs are key APCs in immune regulation, activating both innate and adaptive immunity against HPV through antigen presentation via MHC class I and II pathways. DC-based HPV vaccines have shown promise, particularly with HPV16/18 E7 antigens, in inducing targeted T-cell responses in cervical cancer patients [58]. Strategies like incorporating shRNA to silence SOCS1 in DCs enhance vaccine efficacy by supporting Th1 responses, DC activation, and promoting IFN-γ function [59]. Studies using SOCS1-silenced DC vaccines show improved anti-tumor immunity in models, indicating potential for stronger immunotherapeutic effects.

Adoptive T cell therapy (ACT), or T cell-based vaccines, involves extracting a patient’s T cells, expanding or modifying them ex vivo to recognize tumor antigens, and reinfusing them to target tumors. Strategies include are tumor-infiltrating lymphocytes (TILs), TCR-engineered T cells, and chimeric antigen receptor (CAR)-T cells. Efforts to target HPV-specific antigens (E6, E7) have shown limited success in advanced stages though T cells are important for tumor regression [60]. Unlike traditional vaccines, ACTs bypass host APCs, modifying T cells to overcome immune tolerance [61]. Challenges include risks of cytokine release syndrome (CRS), neurotoxicity, and the need for lymphodepletion. Despite these limitations, ACT’s personalized approach holds significant promise for future cancer treatment [62].

TILs are T cells derived from tumors, expanded ex vivo, typically in the presence of IL-2 to support selection for tumor antigen reactivity, and then reinfused into the patient. TIL therapy has been explored in cancers such as gastrointestinal, lung, and HPV-associated malignancies. TILs targeting HPV oncogenes E6 and E7 have shown tumor regression in metastatic cervical cancer patients. A preclinical study that isolated and expanded HPV E6-reactive T cells from cervical tumor-draining lymph nodes for potential clinical application. A phase 2 clinical trial demonstrated objective responses in 3/9 patients with HPV-associated cancers using E6/E7-reactive TILs post-lymphodepletion and aldesleukin administration [60]. While the TILs were chosen for their reactivity to HPV-specific antigens, cervical cancer cells may also express additional tumor antigens which could have been a possible target for these expanded T cells. Future research utilizing TILs that are exclusively HPV-specific could clarify whether tumor regression was solely a result of targeting HPV antigens [63]. An alternative to TILs, cytokine-induced killer (CIK) therapy, uses expanded peripheral blood mononuclear cells (PBMCs) rather than tumor-infiltrating immune cells [64]. This approach simplifies tumor targeting while sparing most healthy tissue and has shown efficacy in both solid and hematologic cancers. In cervical cancer, CIK therapy combined with CRT showed short-term effectiveness, supporting further research into its application [65]. Despite this promise, TIL therapy is labour-intensive, with low success rates and limited effectiveness in highly immunosuppressive TME.

Engineered TCR therapy expands existing tumor-specific T cells, TCR therapy involves genetically modifying host-derived T cells to express specific TCRs that target tumor antigens unlike TIL therapy. This approach bypasses the immune tolerance typically exhibited by tumors. The cloned, tumor-specific TCR T-cells recognize specific antigen peptides presented by MHC I/II molecules and are reinfused into the patient after expansion [66]. The efficacy of TCR therapy hinges on the successful generation of TCR α and β chains that can effectively bind to tumor targets and their expression in autologous T cells. The identification of tumor cells by engineered TCR cells depends on the abundance of the α/β heterodimer on the cell surface and the receptor’s affinity for the target antigen. Strategies such as modified promoters or mutations in the α and β chains may enhance the effectiveness of engineered TCR T cells [61]. Recent studies suggest that these engineered TCR T cells can recognize E6 and E7-positive tumor cells. A phase 1/2 trial evaluated E6-engineered TCR T cells in HPV16+ cancers, administered alongside lymphocyte depletion and IL-2 [67]. The results indicate that E6 TCR therapy may induce regression in HPV-associated epithelial cancers, warranting further investigation. Multiple ongoing clinical trials are assessing the use of HPV oncoprotein TCR T cells in cervical cancer, with completion expected in the coming years (NCT02858310: E7 TCR T-Cells for HPV-Associated Cancers). Despite these efforts, most successes with TCR therapies have been seen in hematologic malignancies, and the overall therapeutic effects on solid tumors and HPV-associated cancers remain largely unexplored [68].

CAR-T cell therapy involves genetically modifying T cells to enhance their specificity for tumor antigens through the introduction of a synthetic recognition structure known as CAR. A key advantage of CAR-T cell therapy is its independence from functional MHC presentation system on cancer cells, which is significant in immunosuppressive TME where MHC expression may be downregulated [69]. Hence, CAR-T cells can potentially eradicate tumors that may not effectively present antigens, unlike TILs, TCR therapies, or traditional immunotherapeutic vaccines. The CAR design consists of an extracellular antigen recognition domain derived from a single-chain variable fragment (scFv) of a mAb, a hinge domain, a transmembrane domain, and an intracellular signalling domain [70]. This structure provides essential co-stimulatory signals necessary for activating effector T cells.

Despite promising results in haematological cancers—such as the FDA-designated “breakthrough” CD19 CAR-T therapy (CTL019), applications in solid tumors, including cervical cancer, are limited due to the highly complex and immunosuppressive TME [71]. Unlike hematologic malignancies, solid tumors present physical barriers such as dense extracellular matrix and irregular vasculature, which hinder CAR-T cell infiltration. Furthermore, cervical cancer often upregulates immunosuppressive molecules like PD-L1 and secretes TGF-β and IL-10, which suppress T-cell activity and proliferation. The TME is enriched with Tregs, myeloid-derived suppressor cells, and tumor-associated macrophages that further dampen the immune response. Additionally, antigen heterogeneity in cervical tumors can lead to immune escape, as tumor cells lacking the targeted antigen can survive and proliferate. These challenges necessitate strategies such as TME-modifying agents, dual-targeting CAR-T cells, or combining CAR-T therapy with ICI to improve efficacy against cervical cancer. Currently, an ongoing Chinese trial is investigating CAR-T cells targeting GD2, PSMA, Muc1, or mesothelin in cervical cancer patients, instead of majority of trials focussing on HPV antigens (NCT03356795).

Despite the promise of immunotherapy in cervical cancer, several challenges hinder its broad adoption. PD-L1 is an imperfect biomarker, necessitating better predictive markers for patient selection [72]. Immune-related AE (irAE), ranging from mild to severe, require vigilant monitoring, with some cases needing treatment discontinuation. Response rates are limited, with some patients showing no benefit, highlighting the need to understand resistance mechanisms. Additionally, the high cost of immunotherapy restricts access, particularly in low-resource settings where cervical cancer incidence is highest, posing significant equity challenges in care delivery [73, 74].

In this era of precision oncology, customized treatments aim to enhance the effectiveness of anticancer drugs by limiting their systemic exposure and focusing on specific molecular markers expressed uniquely by cancer cells. This approach minimizes off-target effects, providing a more targeted and safer therapy and here comes the role of antibody-drug conjugates (ADCs). ADCs combine the precision of a mAb targeting tumor-specific antigens with a cytotoxic chemotherapeutic drug, linked via a chemical bond. The mAb directs the ADC to tumor cells, where it releases its drug payload in the lysosome, leading to targeted cell death through apoptosis or DNA/microtubule disruption [75]. ADCs also exhibit a bystander effect, affecting nearby cells, and modify the TME, bypassing immune suppression mechanisms that often hinder immune-based therapies. ADCs improve target specificity by using antibodies to selectively bind antigens expressed on tumor cells, minimizing off-target effects on healthy tissues. This targeted approach enables the delivery of highly potent cytotoxic drugs directly to cancer cells, overcoming limitations like low therapeutic indices of traditional chemotherapy. Unlike immune-based therapies that rely on an intact immune system, ADCs are less affected by immune evasion strategies, such as PD-L1 overexpression or T-cell exhaustion. By targeting specific tumor antigens and employing cytotoxic payloads, ADCs offer an effective alternative or complement to existing immunotherapies, particularly in cancers with poor immune visibility or resistance to ICI. Tisotumab vedotin (TV) targets tissue factor on cervical cancer cells, using monomethyl auristatin E (MMAE) to cause G2/M arrest and cell death [76, 77].

One primary challenge is achieving sufficient immune cell, antibody, and drug penetration throughout the TME. For instance, CAR-T cells show efficacy in hematologic cancers but face obstacles in solid tumors, where access is often limited. Additionally, “cold tumors”, with low lymphocyte infiltration, are less responsive to ICI. This underscores the importance of research to improve immune cell, antibody, and drug delivery to the TME [78, 79].

Advances in strategies to generate antigen-specific T cells and reverse immunosuppression within the TME offer a pathway to enhanced therapies. Challenges remain, including delivering immune cells and drugs effectively across the TME. HPV is a major etiological factor, making it a clear immunotherapy target. It is important to look for biomarkers beyond PD-L1, focusing on tumor mutational burden, microsatellite instability, and immune signatures to enhance patient selection. Combining immunotherapy with chemotherapy, targeted therapies, or RT may improve response rates and overcome resistance. Personalized immunotherapy, tailored to individual genetic and immune profiles, could optimize efficacy while minimizing toxicity, marking a shift toward more precise and effective treatments.

Immunotherapy has significantly expanded the treatment landscape for cervical cancer, offering new hope to patients across various stages of the disease. In the neoadjuvant and adjuvant settings, its role remains investigational, while in the concurrent and metastatic/recurrent settings, ICI have already demonstrated clinical benefits, leading to regulatory approvals. As research continues to advance, combining immunotherapy with other therapeutic strategies and identifying predictive biomarkers will be essential to maximizing its potential. Although challenges remain, the promise of immunotherapy in improving the prognosis of cervical cancer patients is becoming increasingly evident.