Immunotherapies for Ovarian Cancer Treatment

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Lubna Najm

Ovarian cancer is one of the top ten most common malignancies to affect women and females worldwide (NIH National Cancer Institute, 2025; Wang et al., 2025), with a 51.6% five-year survival rate (NIH National Cancer Institute, 2025). Named the ‘silent killer’ amongst women-prevalent diseases because its symptoms are either difficult to distinguish from other conditions or are altogether lacking, as well as the limited early-stage diagnostic health tools available (Georgia’s Online Cancer Information Center, 2025; Johnson et al., 2021). As a result, women, females and transgender individuals often do not receive a diagnosis until the disease has significantly progressed to advanced stages (Huang et al., 2022; Johnson et al., 2021; Wesp, 2016).

Current gold standard treatment strategies implemented by health care professionals can be highly invasive and non-specific to the location of the cancer (Huang et al., 2022; Johnson et al., 2021). Due to the systemic nature of these widely used clinical treatments, not only are there associated severe side effects that can occur throughout the body, such as neurotoxicity, fatigue, hair loss, or damage to the immune system, but there is high probability of recurrence or relapse (Demircan et al., 2020; Siminiak et al., 2022; Woopen et al., 2023). Examples of these clinical treatments include chemotherapies, such as platinum-based or neoadjuvant chemotherapy, and surgeries, such as primary or interval debulking surgery (Wang et al., 2025). Thus, taking a non-specific approach to ovarian cancer treatment is often not as effective as a first-line treatment strategy (Demircan et al., 2020; Siminiak et al., 2022).

Targeted treatments have gained traction as they can minimize side effects, toxicity and
recurrence associated with systemic treatments that are non-specific. However, treatments such as poly (ADP-ribose) polymerase (PARP) inhibitors and antibody-drug conjugates (ADCs), while being more targeted and less invasive, can promote or induce acquired resistance after prolonged use, making them ineffective for long term treatments (Luo et al., 2024; Wang et al., 2025).

Due to these limitations in ovarian cancer clinical diagnostics and treatment, the quality of life and long-term outlook are negatively impacted for those with ovarian cancer (Huang et al., 2022; Johnson et al., 2021; Wang et al., 2025). Nonetheless, advancement in biotechnology and cancer treatments has significantly contributed to the decline of ovarian cancer-related deaths worldwide by an average of 1.6% annually over the past 10 years (NIH National Cancer Institute, 2025).

This article dives into the immunology, development status, and future steps of targeted treatments that can overcome acquired resistance and have high potential to further enhance the long-term outcomes of females and women with ovarian cancer.

Prognosis and Characteristics of Ovarian Cancer

Ovarian cancer is a multifaceted condition, affecting multiple aspects of gynecological health and wellbeing, such as tissue, hormones, and immune cell responses (Canadian Cancer Society, 2025a; Wang et al., 2025). Different cancers exist that can target the epithelial lining, endometrial lining, and fallopian tubes. In rare cases, ovarian cancers can occur in the stromal cells that make up ovarian connective tissue, or germ cells, the precursors of eggs (Canadian Cancer Society, 2025a). For both women and transgender individuals, ovarian cancer can affect sex hormones by creating an imbalance, which is known to maintain and promote ovarian tumour growth (Canadian Cancer Society, 2025b; Wesp, 2016). Ovarian cancer is also characterized by thick, solid cancerous tissues, impacting the functions of the ovary in protecting and preserving eggs, which subsequently is associated with higher instances of infertility (Canadian Cancer Society, 2025a; Wang et al., 2025).

Inherently, ovarian cancer is an immunogenic cancer, whereby it leverages its tumour microenvironment (TME) to promote and facilitate ovarian tumourigenesis, angiogenesis and metastasis. The ovarian TME also suppresses immune cell responses, particularly CD8+ T Cells (Ghisoni et al., 2024; Gu et al., 2024; Wang et al., 2025). As such, future innovations in ovarian cancer treatment strategies are shifting towards immunotherapies to eliminate the cancer by leveraging or addressing these key tumour-immune cell interactions and interfaces (Ghisoni et al., 2024; Gu et al., 2024). Another benefit of emerging immunotherapies is that they bypass the acquired resistance that occurs with PARP inhibitors and ADCs (Wang et al., 2025).

Immunotherapies for Ovarian Cancer Treatment

Of the emerging immunotherapies currently in development, the three most promising include immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell (CAR T-cell) therapy, and tumor vaccination (Ghisoni et al., 2024; Wang et al., 2025).

Ovarian tumor cells evade the immune system by targeting key pathways in the induction and promotion of CD8+ T-cells. Specifically, tumor cells suppress killer T-cell activity by promoting cell death ligand 1 (PD-L1) expression on tumor cell surfaces, which allows the tumor cells to interact with programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) found on the surfaces of T cells. Promoting these ligand and protein interactions disrupts the activation of T cells and suppresses them, thus facilitating tumor suppression (Wang et al., 2025).

To combat this immune system evasion mechanism, ICIs are highly specific monoclonal antibodies that block the interaction of PD-L1 with PD-1 and CTLA-4. Examples include anti-PD-L1, anti-PD-1, and anti-CTLA-4, with common names, pembrolizumab, atezolizumab, and ipilimumab. Often, these ICIs are combined with one another to target multiple pathways simultaneously. However, one key drawback of ICIs is their ability to develop acquired antibiotic resistance, resulting in decreased effectiveness over time (Wang et al., 2025).

CAR-T cell therapy is a promising alternative to ICIs as they do not result in acquired resistance, allowing for longer maintained effectiveness. Here, T cells from individuals with ovarian cancer are collected, undergo genetic modification, and are re-introduced. These genetically modified T cells are designed to not only recognize tumor cells, but to eliminate them by targeting antigens expressed on the ovarian tumor. Examples of such antigens include mesothelin, human epidermal growth factor receptor 2, glypican-3, and folate receptor alpha. In recent years, CAR-T cells have also been designed to secrete nanoparticles or nanobodies to also target similar pathways as ICIs, such as PD-1 nanobodies (Ghisoni et al., 2024; Wang et al., 2025).

Regardless, CAR-T cell therapies are limited in highly advanced cases of ovarian cancer, as the dense stroma and solid TME make it difficult to the CAR T-cells to infiltrate the tumor, and can result in T-cell exhaustion. A novel way to combat this challenge is to administer the CAR T-cells intraperitoneally, rather than intravenously, for more localized delivery and enhanced infiltration (Wang et al., 2025).

Another limitation CAR-T therapy faces in ovarian cancer treatment is the possibility of developing cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). To mitigate the potential cytotoxicity of CAR T-cells, tumor vaccines are being explored for more localized and targeted therapeutic delivery, which allows for therapeutic stimulation only at the site of the tumor. These vaccines can be derived from immune cells that stimulate T cells, such as vaccines derived from dendritic cells (Wang et al., 2025).

Other immunotherapies are being explored that leverage oncolytic viruses, such as olvimulogene nanivacirepvec (Olvi-Vec), or engineered cytokines, such as nemvaleukin alfa, an IL-2 cytokine that has been designed to target IL-2 receptors on regulatory T-cells (Tregs). The key benefit of biomarker-based technologies especially is their ability to be highly personalized to the individual. These immunotherapies also show promise as enhancements or supplements to not only other immunotherapies but also clinically practiced treatments (i.e. chemotherapy, ADCs, PARP inhibitors) to enhance their effectiveness (Ghisoni et al., 2024; Gu et al., 2024; Wang et al., 2025).

These immunotherapy innovations and technologies, however, are still in early stages, with many still in early-stage clinical trials or preclinical phases. Future steps in this area also include addressing barriers to entry to bring these technologies to clinics for diverse populations of women, such as those from vulnerable groups or low socioeconomic standing that are at the highest risk of ovarian cancer (Johnson et al., 2021). Achieving this would ensure the health disparity gaps faced by diverse populations of women are bridged for more equitable, affordable ovarian cancer treatment and patient care.

Header Image Source: Created by Jessica Desamero with Canva.com

Edited by Shaniqua A. Lawson

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