The review, conducted by researchers at Shiraz University of Medical Sciences, Tehran University of Medical Sciences and University College London, followed the PRISMA 2020 guidelines and searched PubMed, Scopus, Web of Science and Embase for studies published up to September 2025. The team’s protocol was prospectively registered in the PROSPERO database. From the initial search, twenty-four preclinical studies met the inclusion criteria: animal models in which investigators assessed distant tumor regression or systemic immune activation following PDT, whether delivered alone or in combination with other therapies.

The findings were strikingly consistent. Across the included studies, PDT reliably produced local tumor regression and activated the immune system, with the molecular fingerprints of immunogenic cell death clearly visible. Dying tumor cells released damage-associated molecular patterns, exposed calreticulin on their surfaces, and recruited cytotoxic CD8-positive T lymphocytes into the tumor microenvironment. These are the same hallmarks that immunologists look for when a cell death event is capable of training the adaptive immune system to recognize and attack cancer, rather than simply clearing debris.

The abscopal effect itself, named from ‘ab’ meaning away and ‘scopal’ meaning target, has historically been a rare and unpredictable curiosity in radiation oncology. When it occurs, a localized treatment appears to prime immune cells that then travel through the circulation and attack tumors that were never irradiated. For decades, clinicians reported it only sporadically, and its rarity made it difficult to study. The new review suggests that PDT may offer a more controllable way to induce this systemic response, because the therapy’s oxidative burst can be tuned by adjusting drug dose, light intensity, timing and photosensitizer chemistry.

Crucially, the strongest abscopal responses emerged when PDT was paired with immune checkpoint blockade, specifically antibodies targeting programmed cell death protein-1, or PD-1, and its ligand PD-L1. Checkpoint inhibitors release the molecular brakes that tumors place on T cells, and the review’s authors found that combining them with PDT’s immune-priming effect produced clear distant tumor regression in several animal studies. Adjuvants, substances that boost immune signaling, also amplified the systemic response when co-administered with the light treatment. This synergy makes mechanistic sense: PDT floods the tumor with antigens and danger signals, while checkpoint blockade ensures the newly activated T cells are not silenced as they circulate.

The systemic nature of the immune activation was confirmed at the molecular level. Multiple studies reported upregulation of key inflammatory cytokines, including interleukin-6, interferon-gamma and tumor necrosis factor-alpha, in the circulation of treated animals. These signaling molecules are characteristic of a robust, body-wide immune response rather than a purely local inflammatory reaction. Interferon-gamma in particular is central to antitumor immunity, enhancing antigen presentation and directly inhibiting tumor cell proliferation, while tumor necrosis factor-alpha contributes to vascular disruption within tumors and supports cytotoxic lymphocyte function.

What distinguishes PDT from radiotherapy, its closest conceptual rival for abscopal induction, is the nature of the cell death it provokes. Reactive oxygen species generated by the photosensitizer can trigger immunogenic apoptosis and necrosis while preserving tumor antigen integrity, and PDT can also damage tumor vasculature and reprogram the immunosuppressive tumor microenvironment. The review notes that immune reprogramming, the shift of a tumor from a cold, T-cell-excluded state to a hot, inflamed state, appears to be a key mechanism by which PDT converts a local treatment into a systemic one. By depleting suppressive myeloid cells and regulatory T cells and promoting dendritic cell maturation, PDT can create the conditions under which newly primed T cells can function effectively.

The authors are careful to frame their conclusions as preclinical, with early clinical studies offering preliminary support but not definitive proof. Animal models of cancer frequently overstate immune effects that later fail to translate into human trials, and the twenty-four studies included in the review varied in photosensitizer, tumor model, light dosing and combination regimens, making direct comparison difficult. The review nonetheless argues that the consistency of the immune activation signals across models, and the reproducibility of abscopal responses when PDT is combined with checkpoint blockade, justify moving the field toward carefully designed clinical evaluation. Optimizing treatment parameters, the authors suggest, may allow PDT to evolve from a local, cytotoxic treatment into a genuine systemic cancer immunotherapy.

The implications for patients with metastatic disease are considerable. If a clinician could illuminate a single accessible lesion and thereby vaccinate the patient’s immune system against their own tumor, the strategy could complement existing immunotherapies rather than replace them. Combination trials pairing PDT with PD-1 or PD-L1 inhibitors are the most obvious next step, and the review’s systematic synthesis of preclinical evidence provides a roadmap for which parameters, photosensitizers and adjuvant strategies appear most promising. Questions remain about the durability of the induced immunity, the risk of immune-related adverse events, and whether human tumors, which are more heterogeneous than laboratory models, will respond as predictably.

For now, the review stands as the most comprehensive preclinical assessment to date of PDT’s ability to reach beyond the beam of light that delivers it. It documents a therapy long thought of as surgically precise quietly revealing a second identity: an immune catalyst capable of sending signals far beyond the treated site. As the authors conclude, with optimized parameters and rational combinations with immunotherapy, photodynamic therapy may develop from a local cytotoxic tool into a systemic weapon against cancer, one that turns a single illuminated tumor into the trigger for a body-wide immune campaign.

Subject of Research: Systematic review of preclinical evidence that photodynamic therapy induces immunogenic cell death and abscopal, systemic antitumor immune responses

Article Title: Immunogenic and systemic antitumor responses induced by photodynamic therapy: a systematic review of the abscopal effect

Article References: Faghani-Eskandarkolaei, P., Zareei-khooshab, V., Mansouri-Bidekani, R., Heli, H., Abdollahi, M., Haghighi, H., Zahraie, N., & Sattarahmady, N. (2026). Immunogenic and systemic antitumor responses induced by photodynamic therapy: a systematic review of the abscopal effect. Cancer Cell International. https://doi.org/10.1186/s12935-026-04455-4

Image Credits: AI Generated

DOI: 10.1186/s12935-026-04455-4

Keywords: photodynamic therapy, abscopal effect, immunogenic cell death, reactive oxygen species, immune checkpoint blockade, CD8-positive T lymphocytes, calreticulin, damage-associated molecular patterns, cytokines, tumor microenvironment, cancer immunotherapy, metastatic cancer

Cervical cancer is largely preventable through vaccination against human papillomavirus and detectable early through screening, yet it remains a major source of cancer deaths worldwide, particularly in low- and middle-income countries where screening programs are limited. For the subset of women whose disease recurs after treatment of the primary tumor or who present with metastatic disease at diagnosis, prognosis has historically been bleak. The mainstay of treatment for decades was combination chemotherapy, with or without the anti-angiogenic agent bevacizumab, which could slow the disease temporarily but rarely produced long-term control. Median survival in this setting had for years remained measured in months rather than years.

That landscape began to shift as researchers recognized that cervical cancer, despite being a virally driven malignancy, had characteristics that made it potentially susceptible to immune checkpoint blockade. Pembrolizumab, a monoclonal antibody that blocks the programmed cell death protein 1, or PD-1, receptor on T cells, releases a molecular brake that tumors use to disable the immune response. By preventing PD-1 from engaging its ligands, the drug allows cytotoxic T lymphocytes to recognize and attack tumor cells. The rationale for testing the drug in cervical cancer was reinforced by the observation of tumor-associated T-cell infiltration and the activity of pembrolizumab as a single agent in previously treated patients, which paved the way for a definitive test in the first-line, untreated setting.

KEYNOTE-826, the trial behind the new analysis, enrolled patients with persistent, recurrent, or metastatic cervical cancer who had not previously received systemic chemotherapy for their advanced disease. Participants were randomly assigned to receive their physician’s choice of standard chemotherapy, with or without bevacizumab, either alone or in combination with pembrolizumab. The trial used a double-blind, placebo-controlled design, meaning that neither patients nor the investigators assessing outcomes knew which treatment arm each patient had been assigned to, a rigor that strengthens the reliability of the comparisons. The study was stratified in ways that reflected known prognostic variables, including the use of bevacizumab, prior exposure to radiotherapy, tumor histology with separate accounting for squamous and adenocarcinoma subtypes, and PD-L1 expression status as determined by a validated combined positive score.

The initial reports of the trial demonstrated statistically significant and clinically meaningful improvements in the co-primary endpoints of overall survival and progression-free survival, along with higher response rates, among patients receiving pembrolizumab plus chemotherapy compared with chemotherapy alone. Those results led to regulatory approvals in the United States and elsewhere and changed practice guidelines internationally. Immunotherapy combinations, however, carry a distinctive uncertainty: unlike cytotoxic chemotherapy, whose effects are usually immediate and short-lived, immune-mediated responses can be durable but take time to fully manifest. The central question addressed by extended follow-up is whether the survival curves remain separated over many years, whether a meaningful fraction of patients remain progression-free long after treatment ends, and whether late toxic effects erode the benefit.

The five-year data reported in the new analysis provide reassurance on all three counts. The separation between treatment arms observed in earlier interim analyses persisted with longer follow-up, and the durability of benefit supports the interpretation that the early advantage was not an artifact of immature data. Patients with PD-L1-positive tumors, who represent the majority of those with advanced cervical cancer, derived particular benefit, consistent with the biological expectation that checkpoint blockade works best when the tumor microenvironment already harbors an immune response that has been suppressed rather than one that is absent altogether. The analysis also confirmed that the safety profile remained consistent with what had been established previously, without the emergence of concerning late-onset adverse events that would complicate the risk-benefit calculus.

For clinicians treating gynecologic cancers, the confirmation matters because it removes lingering doubt about whether to incorporate pembrolizumab into first-line treatment. When overall survival benefits are demonstrated at interim analyses with limited follow-up, some physicians defer adoption pending proof of durability, particularly when the regimen adds cost, requires regular infusions, and carries the risk of immune-related adverse events affecting organs such as the thyroid, lungs, colon, and kidneys. Five-year data showing that patients who received the combination were still alive and, in some cases, still without disease progression years after randomization provide the kind of evidence that persuades even cautious practitioners and health systems to make the regimen standard of care.

The findings also carry implications for how the field moves forward. With an immunotherapy-chemotherapy backbone now established as the foundation of first-line treatment for recurrent and metastatic cervical cancer, research attention is turning to questions the original trial was not designed to answer. These include whether biomarkers beyond PD-L1 expression can identify which patients stand to benefit most, whether the addition of bevacizumab is necessary for all patients or can be reserved for selected groups, whether novel agents such as antibody-drug conjugates can be layered onto the regimen safely, and whether patients who achieve long-term disease control can safely discontinue treatment. Trials exploring tissue-agnostic and site-specific combinations are already underway, building on the platform that KEYNOTE-826 validated.

There are limits to what even long-term randomized data can resolve. The exploratory nature of this analysis means that some subgroup findings should be interpreted with caution, as smaller patient numbers reduce statistical power and increase the chance that observed differences reflect chance rather than biology. Access remains a critical concern: pembrolizumab is expensive, and the populations with the highest burdens of cervical cancer often live in health systems where the drug is least available. Translating a five-year survival benefit demonstrated in an international trial into widespread clinical reality requires attention to drug pricing, health infrastructure, and the upstream interventions of HPV vaccination and screening that prevent advanced disease in the first place.

Nevertheless, the five-year results represent a milestone for a disease that, until recently, offered patients with recurrence little hope of extended survival. The demonstration that benefit endures converts an important interim finding into a settled standard and provides a reference point against which all future therapies for advanced cervical cancer will be measured. For the women treated on the trial, the data translate into years of life that would likely have been lost under the previous standard, and for the broader oncology community, they reinforce a principle that has gradually reshaped cancer medicine: when the immune system can be durably unleashed against a tumor, the benefits can outlast the treatment itself. The corresponding author of the analysis is Kosei Hasegawa, MD, PhD, of the Department of Gynecologic Oncology at Saitama Medical University International Medical Center in Japan, and the findings were published in JAMA Oncology under DOI 10.1001/jamaoncol.2026.3547.

Subject of Research: Pembrolizumab combined with chemotherapy as first-line treatment for recurrent and metastatic cervical cancer

Article Title: Pembrolizumab plus chemotherapy for cervical cancer

Article References: Pembrolizumab plus chemotherapy for cervical cancer. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: cervical cancer, pembrolizumab, KEYNOTE-826, immunotherapy, PD-1 inhibitor, chemotherapy, bevacizumab, JAMA Oncology, metastatic cancer, clinical trial, overall survival, gynecologic oncology