The motivation behind the work was elegant in its simplicity. Somatic mutations in the CALR gene produce oncogenic calreticulin variants that drive certain myeloproliferative neoplasms by binding the thrombopoietin receptor MPL and activating it without ligand. These variants lose their KDEL endoplasmic reticulum retention signal, allowing them to be secreted or displayed on the cell surface. Because calreticulin was believed to be a lectin-like chaperone within the peptide loading complex of MHC class I, and because previous reports had documented decreased MHC class I surface expression, defective peptide loading, and an altered presented repertoire in cells expressing oncogenic calreticulin, the authors hypothesized that oncoCALR might be a uniquely sinister oncogene, one that simultaneously induces malignant transformation and immune evasion by corrupting the very machinery the immune system uses to detect it.

To test this hypothesis, the team engineered the murine pro-B cell line Ba/F3, derived from an H-2Kb-negative C3H mouse strain, to express murine MHC class I molecules fused to a mCherry reporter carrying ovalbumin-derived peptides of high, medium, and low binding affinity. These target cells, carrying either wild-type calreticulin, a calreticulin knockout, heterozygous or homozygous oncogenic mutations, or deletions of exon 9, were co-cultured with OT-I T cells that recognize the ovalbumin peptide in the context of H-2Kb. Flow cytometric assessment of the T cell activation marker CD69 after 6 and 24 hours revealed no defects at any time point in any mutant group. Even removal of the N-linked glycosylation sites N86 and N176 from H-2Kb, which should abolish the lectin-mediated interaction between calreticulin and the nascent MHC class I molecule, left antigen recognition by T cells entirely intact.

The researchers then extended their analysis to primary cells. Haematopoietic stem cells harvested from mice carrying oncogenic calreticulin or a calreticulin knockout in their haematopoietic system were lentivirally transduced to present the ovalbumin peptide by their endogenous H-2Kb complex and co-cultured with OT-I T cells for 72 hours. T cell activation, measured as the percentage of CD8-positive CD25-positive cells, and target cell killing were indistinguishable across all genotypes. The team did confirm previous reports of lower surface H-2Kb expression in homozygously oncoCALR-expressing and calreticulin-deficient cells, but this quantitative reduction did not translate into any functional impairment, consistent with the observation that even a single MHC class I molecule can trigger a T cell response through the MHC/TCR interaction.

The most ambitious test came in vivo. The researchers infected mice carrying heterozygous or homozygous oncogenic calreticulin, a calreticulin knockout, or wild-type calreticulin in their haematopoietic system, or in the liver under an AlbCre promoter, with 2 million focus-forming units of lymphocytic choriomeningitis virus strain Armstrong. Eight days post-infection, at the peak of the adaptive immune response, flow cytometric analysis of blood and spleen revealed no significant differences in the relative abundance of effector T cells or LCMV-specific effector T cells across genotypes. Cytokine production of splenic CD8-positive T cells restimulated with the LCMV gp33 peptide was unaltered in calreticulin knockout cells and, remarkably, significantly increased in heterozygous oncoCALR cells, while the cytotoxic protein granzyme B remained steady in all groups. The absence of calreticulin or the presence of its oncogenic variant did not compromise the antiviral T cell response in any organ system examined.

Finally, the team turned to human samples. CD34-positive haematopoietic stem cells were isolated from ten HLA-A02:01-positive and oncoCALR-positive myeloproliferative neoplasm patients and eight HLA-A02:01-positive healthy control donors. These target cells were co-cultured with a Jurkat T cell line engineered to express a chimeric antigen receptor recognizing the endogenous WT1-derived HLA-A*02:01-restricted peptide RMFPNAPYL. WT1 was selected as the antigen because it is equally expressed by healthy donor and patient-derived CD34-positive stem cells. CAR Jurkat activation, measured by CD69 expression after 48 hours, showed only a marginally lower response to patient-derived cells, and the researchers could find no differences in HLA surface expression, WT1 antigen levels, or expression of the T cell-suppressing ligand PD-L1 that would explain this slight decrease. MHC class I function in oncoCALR-expressing human cells was intact or, at most, minimally impaired.

Having failed to demonstrate a pivotal role for calreticulin in MHC class I functionality, the researchers sought to identify what calreticulin actually does at the proteome level. They performed tandem mass tag mass spectrometry on primary murine neutrophil granulocytes and cytotoxic T cells from calreticulin knockout, homozygous oncoCALR, and wild-type mice, restricting their analysis to proteins of the secretory pathway that could potentially interact with the endoplasmic reticulum-based chaperone. Five proteins were absent from samples of both test genotypes and both cell types: acyloxyacyl hydrolase, eosinophil peroxidase, neutral alpha-glucosidase AB, myeloperoxidase, and phospholipidase B-like 1. The abundance of murine MHC class I, H-2Kb, remained steady in the proteome despite its decreased surface expression, likely because the molecule accumulates in the Golgi apparatus rather than being degraded. These findings establish calreticulin as an indispensable chaperone for a specific subset of secretory pathway proteins, but not for MHC class I.

How, then, did calreticulin’s role in MHC class I function become so massively overestimated? The authors point to the history of its discovery. Calreticulin was found associated with MHC class I through co-immunoprecipitation assays from human cell lines in 1996 and later identified as part of the peptide loading complex by cryo-electron microscopy of affinity-purified extracts. The researchers argue that calreticulin, as a lectin chaperone capable of interacting with any glycoprotein bearing a Glc1Man9GlcNAc2 oligosaccharide, likely contaminates affinity purification-based analyses nonspecifically. Indeed, calreticulin is a member of the so-called CRAPome, a repository listing binding partners frequently found in co-immunoprecipitation and mass spectrometry protein interaction studies. Calreticulin may maintain a physical association with MHC class I, but this interaction does not influence its function. Moreover, some HLA alleles have been reported to be completely independent of the entire peptide loading complex.

The implications of this work are considerable. For patients with myeloproliferative neoplasms, the finding that MHC class I functionality is intact in oncoCALR-expressing cells encourages the feasibility of cancer vaccination approaches that previous studies had abandoned, claiming defects in antigen presentation as a cause. The identification of myeloperoxidase and other antibacterial immune proteins as calreticulin-dependent chaperone clients suggests that patients carrying oncogenic calreticulin mutations may harbor a subtle immune defect in the antibacterial response, an area that warrants further investigation. Calreticulin itself remains biologically essential: pan-calreticulin-deficient mice are not viable due to a defect in cardiogenesis, and female mice expressing oncogenic calreticulin homozygously in their haematopoietic system do not breed. The functional role of calreticulin in the peptide loading complex, the authors conclude, now needs to be redefined and its significance reevaluated, a conclusion that will force immunologists to reconsider a molecular relationship they had taken for granted since the mid-1990s.

Subject of Research: The role of calreticulin and its oncogenic variants in MHC class I antigen presentation and T cell immune responses

Article Title: Haematopoietic Cells Deficient for Calreticulin or Expressing Its Oncogenic Variants Maintain Functional Antigen Presentation

Article References: Höhrhan, M., Antonio‐Herrera, L., Colaço, H. G., Wagner, A., Unterwurzacher, M., Varga, C., Kratochwill, K., Bergthaler, A., & Kralovics, R. (2026). Haematopoietic Cells Deficient for Calreticulin or Expressing Its Oncogenic Variants Maintain Functional Antigen Presentation. Journal of Cellular and Molecular Medicine, 30(19), Article e71399. https://doi.org/10.1111/jcmm.71399

Image Credits: AI Generated

DOI: 10.1111/jcmm.71399

Keywords: calreticulin, MHC class I, antigen presentation, myeloproliferative neoplasms, oncogenic CALR mutations, T cell response, peptide loading complex, immunopeptidomics, cancer vaccination, chaperone biology, Haematopoietic, Cells

The strategy rests on a molecular tug-of-war that determines whether a macrophage will engulf a tumor cell. Healthy cells display the surface protein CD47, which engages a receptor on macrophages and delivers a ‘don’t eat me’ signal, protecting normal tissue from collateral destruction. The researchers had previously shown that Ewing sarcoma cells exploit this system by upregulating CD47 while simultaneously downregulating cell-surface calreticulin, an ‘eat me’ signal that normally flags stressed or malignant cells for removal. The tumor, in other words, hides its own alarm while waving a shield. The team’s earlier work showed that blocking CD47 with the antibody magrolimab, while using the chemotherapy drug doxorubicin to push calreticulin back onto the tumor cell surface, dramatically enhanced macrophage phagocytosis of Ewing sarcoma cells in laboratory dishes and suppressed tumor growth and metastasis in an orthotopic mouse model.

That earlier combination, however, carried serious liabilities. Doxorubicin is a cornerstone of Ewing sarcoma treatment, but it is notorious for causing cardiotoxicity, a cumulative injury to heart muscle that can surface years after treatment, a particularly troubling prospect for pediatric survivors. Magrolimab, for its part, binds CD47 on red blood cells, triggering their clearance by the spleen and producing anemia, a side effect that has complicated the clinical development of first-generation anti-CD47 antibodies across the field. The new study set out to answer a deceptively simple question: could the therapeutic principle be preserved while swapping out the components responsible for the worst toxicities?

The first step was diagnostic. The researchers performed single-cell RNA sequencing on cells isolated from Ewing sarcoma xenograft tumors that had been treated with a phosphate buffer control, doxorubicin alone, magrolimab alone, or the doxorubicin plus magrolimab combination. Single-cell transcriptomics allows investigators to profile gene expression in individual cells rather than in bulk tissue, revealing how each cell type within the tumor microenvironment responds to therapy. The results were sobering: doxorubicin, whether given alone or with magrolimab, upregulated cellular pathways and functions associated with dilated cardiomyopathy in macrophages. The sequencing data suggested that the very drug used to sensitize the tumor to immune attack was simultaneously driving molecular changes in the tumor-associated immune compartment consistent with heart muscle disease, reinforcing the need for an alternative partner drug.

The team turned to cyclophosphamide, another standard chemotherapy agent for Ewing sarcoma, as a candidate replacement for doxorubicin. In a series of dose-response experiments, cyclophosphamide significantly enhanced cell-surface calreticulin expression on Ewing sarcoma cells in a dose-dependent manner, replicating the key sensitizing effect of doxorubicin without its cardiomyopathy-associated transcriptional signature. This matters because calreticulin exposure is the mechanistic linchpin of the approach: when the ‘eat me’ signal reappears on the tumor surface, CD47 blockade tips the balance decisively toward phagocytosis. The finding established that the dual-targeting logic of the therapy could be maintained with a chemotherapy agent already familiar to pediatric oncologists.

The second substitution addressed the anemia problem. Rather than magrolimab, the researchers tested lemzoparlimab, a next-generation anti-CD47 antibody engineered to spare erythrocytes. First-generation antibodies such as magrolimab bind CD47 indiscriminately, and because red blood cells are among the most CD47-abundant cells in the body, they are cleared en masse, producing the anemia that has limited dosing in clinical trials. Lemzoparlimab was designed with modified binding properties that reduce its interaction with red blood cells while preserving high-affinity blockade of CD47 on tumor cells. In in vitro phagocytosis assays, combining cyclophosphamide with either lemzoparlimab or magrolimab markedly increased macrophage engulfment of Ewing sarcoma cells, confirming that the newer antibody retained full functional potency in the presence of the calreticulin-inducing chemotherapy.

The decisive tests came in living animals. Using orthotopic Ewing sarcoma xenograft mouse models, in which tumors are established in the anatomically relevant site rather than under the skin, the researchers evaluated cyclophosphamide combined with magrolimab or lemzoparlimab in immunodeficient NSG hosts. Both combinations significantly reduced tumor growth and lung metastasis while prolonging animal survival compared with controls. These results demonstrated that swapping doxorubicin for cyclophosphamide did not sacrifice the anti-tumor and anti-metastatic efficacy that had made the original combination so compelling, and that either anti-CD47 antibody could deliver the phagocytic signal when paired with the calreticulin-inducing chemotherapy.

Safety, however, could only be properly assessed in a model with a functioning human hematopoietic system. In humanized NSG mice, mice engrafted with human immune and blood-forming cells, the difference between the two antibodies became stark. The cyclophosphamide plus magrolimab combination induced severe anemia and animal death, mirroring the red blood cell toxicity predicted from the antibody’s mechanism. The cyclophosphamide plus lemzoparlimab combination, by contrast, was well tolerated: treated animals maintained their blood counts, showed significantly reduced tumor burden, and enjoyed extended survival. The side-by-side comparison in humanized hosts provides unusually direct preclinical evidence that the erythrocyte-sparing design of lemzoparlimab translates into a genuine safety advantage in the context of this combination therapy.

The significance of the work extends beyond Ewing sarcoma itself. The CD47-calreticulin axis is exploited by a wide range of malignancies, and the field has struggled to reconcile the potent anti-tumor activity of CD47 blockade with its hematologic toxicity. By demonstrating that a chemotherapy agent can be selected not only for tumor-killing activity but for its ability to induce calreticulin without cardiomyopathy-associated transcriptional changes, and that an erythrocyte-sparing antibody can substitute for a first-generation blocker without loss of efficacy, the study offers a template for rational optimization of innate immunotherapy combinations. The use of single-cell RNA sequencing to monitor off-target pathway activation in the tumor microenvironment also illustrates how transcriptomic surveillance can flag toxic liabilities before they reach patients.

The authors caution that the findings remain preclinical, and the road from humanized mouse models to pediatric clinical trials involves regulatory, dosing and scheduling questions that animal studies cannot fully answer. Still, the combination of cyclophosphamide and lemzoparlimab brings together two agents with existing clinical pedigrees, one a decades-old standard of care in Ewing sarcoma and the other an antibody already advancing through oncology trials, which may ease the path to translation. For a disease in which new options for relapsed and metastatic patients are desperately needed, a safe and effective way to turn macrophages against the tumor represents a meaningful step forward. The research was supported in part by the National Cancer Institute Cancer Moonshot and the Children’s Cancer Fund, and the published data, the authors conclude, position the cyclophosphamide plus lemzoparlimab regimen as a therapeutic strategy with high potential for clinical translation in patients with Ewing sarcoma.

Subject of Research: Combinatorial macrophage-mediated innate immunotherapy with cyclophosphamide and lemzoparlimab for Ewing sarcoma

Article Title: Optimizing combinatorial macrophage induced innate immunotherapy against Ewing sarcoma

Article References: Luo, W., Zhu, H., Cannon, M. V., Gross, A., Rosenblum, J. M., Bellantoni, A. J., Mo, X., Roberts, R., Cripe, T. P., & Cairo, M. S. (2026). Optimizing combinatorial macrophage induced innate immunotherapy against Ewing sarcoma. Journal of Experimental & Clinical Cancer Research. https://doi.org/10.1186/s13046-026-03840-1

Image Credits: AI Generated

DOI: 10.1186/s13046-026-03840-1

Keywords: Ewing sarcoma, macrophages, CD47 blockade, lemzoparlimab, cyclophosphamide, calreticulin, magrolimab, immunotherapy, single-cell RNA sequencing, humanized mouse model, pediatric cancer, anemia

Pancreatic neuroendocrine tumors are an uncommon but stubborn group of malignancies. Unlike the more familiar pancreatic adenocarcinomas, they often express high levels of somatostatin receptors on their surface, a molecular feature that has made them eligible for peptide receptor radionuclide therapy. In this approach, a hormone-like peptide called DOTATATE binds to those receptors and delivers a radioactive payload, lutetium-177, directly into tumor cells. The beta radiation released by lutetium-177 travels only a few millimeters in tissue, damaging DNA and triggering cell death in tumor cells while largely sparing surrounding healthy tissue. Clinical trials have shown meaningful benefit, but responses are rarely complete, and resistance eventually develops in many patients.

Sunitinib, meanwhile, is a multitargeted oral kinase inhibitor that blocks several receptors involved in tumor angiogenesis, including vascular endothelial growth factor receptors and platelet-derived growth factor receptors. By starving tumors of their blood supply and directly inhibiting survival signaling within tumor cells, sunitinib has extended progression-free survival in patients with advanced pancreatic neuroendocrine tumors. Clinicians have observed that combining sunitinib with 177Lu-DOTATATE appears to produce deeper and more lasting responses, but the biological basis of this synergy remained poorly defined.

The new research set out to test a specific hypothesis: that the combination does more than simply add two cytotoxic effects. Immunogenic cell death is a specialized form of cell demise in which dying tumor cells release or expose a characteristic set of signals, often called damage-associated molecular patterns. These include calreticulin translocated to the cell surface, secretion of ATP, release of high-mobility group box 1 protein, and presentation of tumor antigens on major histocompatibility complex molecules. Together, these signals attract and activate dendritic cells, which then carry tumor antigens to lymph nodes and prime cytotoxic T lymphocytes capable of hunting down residual cancer cells throughout the body.

Using preclinical models of pancreatic neuroendocrine tumors, the investigators showed that each therapy alone induced only limited immunogenic signaling. Sunitinib treatment produced vascular changes and some direct tumor cell stress, while 177Lu-DOTATATE delivered DNA-damaging radiation that killed a fraction of receptor-expressing cells. Neither monotherapy reliably provoked the full repertoire of immunogenic death markers. When the two were combined, however, the picture changed dramatically. Tumor cells exposed to both agents displayed significantly increased surface calreticulin, elevated ATP secretion, and heightened release of high-mobility group box 1 protein into the tumor microenvironment.

The mechanistic studies went further. The researchers found that sunitinib pretreatment increased the expression of entosis-related and autophagy pathways in tumor cells, processes that are known to be required for the calreticulin exposure that defines immunogenic cell death. At the same time, radiation from lutetium-177 inflicted the DNA damage and endoplasmic reticulum stress that serve as the danger signals alerting the immune system. In effect, the kinase inhibitor appeared to prepare tumor cells for a form of death that the radiopharmaceutical then converted into an immunological alarm, transforming what would otherwise be a quiet, non-inflammatory demise into a stimulus capable of recruiting dendritic cells and activating T cells.

The immune consequences were visible within the tumors themselves. Combination-treated tumors showed increased infiltration by CD8-positive cytotoxic T lymphocytes, higher ratios of effector T cells to immunosuppressive regulatory T cells, and evidence of dendritic cell activation. Interferon-gamma signatures were upregulated, indicating that T cells within the tumor microenvironment had been functionally engaged rather than merely present. The researchers also documented reductions in myeloid-derived suppressor cells and markers of tumor-associated immunosuppression, suggesting that the combination remodels the tumor microenvironment in a direction that favors immune attack.

Perhaps the most striking evidence came from experiments in which the researchers depleted specific immune cell populations or blocked key signaling pathways. When CD8-positive T cells were removed, the survival advantage and tumor control conferred by the combination largely disappeared, demonstrating that the adaptive immune response was not an incidental byproduct but a required component of the therapeutic synergy. Similarly, blocking the recognition of damage-associated molecular patterns abrogated the dendritic cell activation and downstream T cell priming. These findings establish the combination as a bona fide inducer of a vaccination-like effect arising from within the tumor itself.

The implications for clinical practice are considerable. Immunogenic cell death has become one of the central concepts in the rational design of combinations with immune checkpoint inhibitors, since checkpoint blockade works best when antitumor T cells have already been primed. The new findings provide a mechanistic rationale for testing 177Lu-DOTATATE and sunitinib together with agents such as PD-1 or PD-L1 inhibitors in pancreatic neuroendocrine tumors, a disease in which immunotherapy alone has so far shown limited activity. Ongoing and planned clinical trials may now incorporate biomarkers of immunogenic cell death, such as serum high-mobility group box 1 levels or tumor calreticulin staining, as pharmacodynamic readouts of whether the combination is successfully igniting antitumor immunity in individual patients.

The study also carries broader lessons for nuclear medicine. Radiopharmaceuticals have often been viewed as precision cytotoxic tools whose benefits are confined to their radioactive range. Work of this kind reinforces an emerging view that targeted radionuclide therapy can function as an in situ tumor vaccine, and that pairing it with agents that modulate tumor cell death pathways, vascular biology, or immune checkpoints can convert localized radiation into systemic immunological control. For patients with pancreatic neuroendocrine tumors, whose treatment options narrow sharply after somatostatin analogs, everolimus, sunitinib, and 177Lu-DOTATATE have been exhausted, the prospect of a combination that teaches the immune system to finish what the drugs begin offers a genuinely new therapeutic direction grounded in a mechanism that can now be measured, monitored, and deliberately enhanced.

Subject of Research: Mechanism of synergy between sunitinib and 177Lu-DOTATATE peptide receptor radionuclide therapy via immunogenic cell death in pancreatic neuroendocrine tumors

Article Title: Immunogenic cell death as a mechanism of synergy between sunitinib and 177Lu-DOTATATE peptide receptor radionuclide therapy in pancreatic neuroendocrine tumors

Article References: Essler, M., Veit, N., Müller, A., Marinova, M., & Kreppel, B. (2026). Immunogenic cell death as a mechanism of synergy between sunitinib and 177Lu-DOTATATE peptide receptor radionuclide therapy in pancreatic neuroendocrine tumors. Cell Death Discovery, 12(1), Article 379. https://doi.org/10.1038/s41420-026-03344-z

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03344-z

Keywords: immunogenic cell death, sunitinib, 177Lu-DOTATATE, peptide receptor radionuclide therapy, pancreatic neuroendocrine tumors, calreticulin, damage-associated molecular patterns, dendritic cells, CD8 T cells, tumor microenvironment, radiopharmaceuticals, immunotherapy synergy

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