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