image: Figure 4. Schematic representation illustrating the multifaceted role of programmed cell death pathways in the diagnosis, treatment, and prognosis of cervical cancer.
Credit: Copyright: © 2026 Kumar. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
“This review proposes that PCD in cervical cancer should be understood not as a series of isolated pathways, but as an interconnected regulatory network that governs both tumor behavior and therapeutic sensitivity.”
BUFFALO, NY — October 29, 2026 — A new review was published in Volume 13 of Oncoscience on September 30, 2026, titled “Programmed cell death pathways in cervical cancer: Cross-talk, HPV-mediated regulation, and therapeutic implications: A narrative review.”
The review examines how human papillomavirus (HPV) alters programmed cell death pathways in cervical cancer, allowing malignant cells to survive, evade immune responses and develop resistance to treatment. By exploring interactions among different cell death mechanisms, the article highlights potential therapeutic strategies to restore cancer-cell susceptibility to destruction and improve responses to existing treatments. However, most emerging approaches remain experimental and require clinical validation.
The review was authored by Naina Kumar, affiliated with the All India Institute of Medical Sciences (AIIMS), Bibinagar, Hyderabad, India.
Cervical cancer remains a major global health challenge, with persistent infection by high-risk HPV types, particularly HPV16 and HPV18, representing its principal cause. Although vaccination, screening and advances in treatment have improved prevention and care, patients with advanced or recurrent disease continue to face treatment resistance and limited therapeutic options.
Programmed cell death (PCD) is a biological process through which damaged, abnormal or unnecessary cells are eliminated through regulated molecular mechanisms. These pathways help maintain tissue health and prevent uncontrolled growth. Cancer cells, however, can interfere with these processes, allowing them to survive despite genetic damage or exposure to anticancer treatments.
The review synthesizes literature published through October 2025, drawing on studies identified through PubMed/MEDLINE, Scopus and Web of Science. It examines how different forms of programmed cell death interact with HPV-related signaling, the tumor microenvironment and emerging therapeutic strategies.
A central focus is apoptosis, the best-characterized form of programmed cell death. This process removes damaged cells through coordinated molecular events involving proteins such as BAX, BCL-2 and caspases. However, cervical cancer cells frequently suppress these signals, allowing them to resist chemotherapy, radiation and other treatments.
High-risk HPV contributes directly to this resistance through two viral proteins, E6 and E7. E6 promotes degradation of p53, a tumor-suppressor protein that normally helps trigger apoptosis in damaged cells. This reduces the activity of pro-apoptotic molecules such as BAX, PUMA and NOXA. Meanwhile, E7 interferes with the retinoblastoma (RB) pathway, disrupting normal cell-cycle control and promoting uncontrolled proliferation.
Together, these mechanisms support cancer-cell survival while influencing other forms of programmed cell death. The review emphasizes that overcoming HPV-associated resistance may require targeting several interconnected pathways rather than restoring apoptosis alone.
One promising alternative is ferroptosis, an iron-dependent form of cell death caused by the accumulation of damaging lipid peroxides. Unlike apoptosis, ferroptosis depends strongly on iron metabolism, oxidative stress and antioxidant defenses involving proteins such as GPX4 and SLC7A11. Disrupting these protective systems may make treatment-resistant cancer cells more vulnerable to destruction.
Experimental studies have demonstrated interactions between ferroptosis and apoptosis. For example, sanguinarine, a plant-derived compound, has been shown to activate both pathways in cervical cancer cells through increased reactive oxygen species (ROS). Inhibiting either pathway can affect the other, suggesting that coordinated activation may strengthen anticancer effects. However, these findings remain preclinical.
The tumor microenvironment also influences ferroptosis. Research discussed in the review shows that tumor-associated macrophages can release extracellular vesicles carrying microRNAs that suppress lipid peroxidation pathways, helping cancer cells resist ferroptotic death. Understanding these interactions could reveal additional ways to overcome treatment resistance.
Other important mechanisms include pyroptosis and necroptosis, two inflammatory forms of programmed cell death. Pyroptosis involves inflammasome activation, inflammatory caspases and gasdermin proteins that form pores in cell membranes. Necroptosis involves signaling through RIPK1, RIPK3 and MLKL, ultimately causing membrane disruption.
These pathways have complex effects on cancer. Under certain conditions, they eliminate malignant cells and stimulate antitumor immune responses. However, persistent inflammatory signaling may also promote tumor growth or immune suppression. Their therapeutic value therefore depends on the biological context and how selectively they can be activated.
The review also discusses PANoptosis, an integrated cell death process involving interactions among pyroptosis, apoptosis and necroptosis. Although investigated in several cancer models, direct evidence in cervical cancer remains limited. Further research is needed to determine whether activating these pathways together could improve treatment outcomes.
Autophagy represents another important regulator of cellular survival and death. This process allows cells to recycle damaged proteins and organelles. In cervical cancer, autophagy may protect tumor cells during metabolic stress, but it can also facilitate apoptosis or ferroptosis by influencing iron availability, lipid metabolism and mitochondrial function.
These opposing effects make autophagy difficult to target. Drugs such as chloroquine and hydroxychloroquine have been investigated as autophagy modulators in combination treatments, but their clinical effectiveness for this purpose in cervical cancer remains uncertain.
The review further examines cuproptosis, a copper-dependent form of regulated cell death associated with mitochondrial protein dysfunction. Preclinical research suggests that manipulating copper-dependent pathways may increase chemotherapy sensitivity. For example, baicalein combined with cisplatin has shown effects involving apoptosis and cuproptosis-related signaling in cervical cancer models.
Additional mechanisms include parthanatos, associated with excessive PARP1 activation following DNA damage; lysosome-dependent cell death, involving the release of destructive lysosomal enzymes; and NETosis, which involves neutrophil extracellular traps that can influence inflammation and metastasis. These pathways offer further research opportunities, although therapeutic applications remain less developed.
Beyond directly eliminating cancer cells, programmed cell death also influences tumor immunity. HPV-associated tumors may evade immune surveillance by altering antigen presentation, interferon signaling and immune checkpoint pathways, including PD-1/PD-L1. These changes can reduce the ability of immune cells to recognize and destroy malignant cells.
An important concept is immunogenic cell death (ICD), in which dying cancer cells release signals that stimulate antitumor immunity. Molecules such as ATP and HMGB1, together with calreticulin exposure on the cell surface, can promote dendritic cell activation and help initiate cytotoxic T-cell responses.
This creates opportunities to combine cell death-inducing treatments with immunotherapy. The review discusses strategies involving ferroptosis-inducing agents, chemotherapy, radiotherapy and immune checkpoint inhibitors. While PD-1/PD-L1 inhibitors already have an established role in selected patients with cervical cancer, combining them with experimental cell death modulators requires further investigation.
The article also highlights potential molecular biomarkers for treatment selection. Gene-expression signatures associated with ferroptosis, pyroptosis, necroptosis and immunogenic cell death have shown associations with patient survival and immune characteristics. However, most require prospective validation before they can reliably guide clinical decisions.
Another proposed direction involves targeting HPV E6 and E7 to restore sensitivity to multiple cell death pathways. Combining these approaches with ferroptosis modulators, PARP-targeted treatments or immunotherapy could potentially improve antitumor responses, although these strategies require direct experimental testing.
“Overall, the future of PCD research in cervical cancer lies not in identifying additional death pathways, but in strategically integrating them into precision oncology frameworks.”
The review emphasizes that translating these findings into clinical practice will require more sophisticated experimental models and validated biomarkers. Three-dimensional tumor organoids, patient-derived models and systems incorporating immune and stromal cells may help researchers better understand how interconnected cell death pathways function within tumors.
Important challenges remain. Many proposed interventions have been tested primarily in cell lines or animal models, while some mechanistic evidence comes from other cancer types. Excessive activation of inflammatory or oxidative pathways may damage healthy tissues, and difficulties involving drug delivery, systemic toxicity and tumor heterogeneity complicate clinical development.
As a narrative review, the article does not present new experimental findings or a quantitative meta-analysis. The available evidence varies in quality and clinical relevance, and many proposed treatment combinations have not been adequately evaluated in humans. Well-designed clinical studies will be essential to determine whether targeting these pathways improves treatment response, survival or other meaningful outcomes.
Overall, the review highlights programmed cell death as an interconnected network linking HPV-mediated cancer development, immune regulation and treatment resistance. Rather than focusing exclusively on apoptosis, the findings support investigating multiple interacting cell death mechanisms as potential therapeutic targets. Integrating these insights with validated biomarkers and existing treatments may eventually contribute to more individualized and effective cervical cancer care.
DOI: https://doi.org/10.18632/oncoscience.677
Correspondence to: Naina Kumar - drnainakumar@gmail.com, (ORCID 0000-0002-5970-6935)
Keywords: cell, cervical cancer, chemotherapy, programmed cell death, tumor microenvironment
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Journal
Oncoscience
Method of Research
Literature review
Subject of Research
Not applicable
Article Title
Programmed cell death pathways in cervical cancer: Cross-talk, HPV-mediated regulation, and therapeutic implications: A narrative review
Article Publication Date
30-Sep-2026
COI Statement
Author has no conflicts of interest to declare.