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Tractable In Vivo Reprogramming of Tumor Cells to Type 1 Conventional Dendritic Cell-like Cells
Published on: August 1, 2025
Irradiated tumor cell-derived microparticles mediate tumor eradication via cell killing and immune reprogramming
Chao Wan1, Yajie Sun1, Yu Tian1
1Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Abstract:
Radiotherapy (RT) is routinely used in cancer treatment, but expansion of its clinical indications remains challenging. The mechanism underlying the radiation-induced bystander effect (RIBE) is not understood and not therapeutically exploited. We suggest that the RIBE is predominantly mediated by irradiated tumor cell-released microparticles (RT-MPs), which induce broad antitumor effects and cause immunogenic death mainly through ferroptosis. Using a mouse model of malignant pleural effusion (MPE), we demonstrated that RT-MPs polarized microenvironmental M2 tumor-associated macrophages (M2-TAMs) to M1-TAMs and modulated antitumor interactions between TAMs and tumor cells. Following internalization of RT-MPs, TAMs displayed increased programmed cell death ligand 1 (PD-L1) expression, enhancing follow-up combined anti-PD-1 therapy that confers an ablative effect against MPE and cisplatin-resistant MPE mouse models. Immunological memory effects were induced.
Insights
Irradiated tumor cell microparticles mediate the radiation-induced bystander effect, inducing cancer cell death and enhancing immunotherapy. This discovery offers new avenues for cancer treatment by exploiting microparticles for broader antitumor effects.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Radiotherapy (RT) is a cornerstone of cancer treatment, but its efficacy is limited by challenges in expanding clinical applications.
- The radiation-induced bystander effect (RIBE) mechanism remains poorly understood and is not therapeutically utilized.
- Microparticles released from irradiated cells are hypothesized to mediate RIBE, potentially offering novel therapeutic strategies.
Purpose of the Study:
- To investigate the role of microparticles released from irradiated tumor cells (RT-MPs) in mediating the radiation-induced bystander effect (RIBE).
- To explore the potential of RT-MPs to induce antitumor effects and modulate the tumor microenvironment.
- To evaluate the therapeutic potential of RT-MPs in combination with immunotherapy.
Main Methods:
- Utilized a mouse model of malignant pleural effusion (MPE).
- Characterized RT-MPs and their effects on tumor-associated macrophages (TAMs).
- Assessed the impact of RT-MPs on programmed cell death ligand 1 (PD-L1) expression in TAMs.
- Investigated the efficacy of combined RT-MP therapy and anti-PD-1 immunotherapy in MPE models.
Main Results:
- RT-MPs were identified as key mediators of RIBE, inducing broad antitumor effects and immunogenic cell death via ferroptosis.
- RT-MPs polarized M2 TAMs to M1 TAMs, altering antitumor interactions within the tumor microenvironment.
- Internalization of RT-MPs by TAMs led to increased PD-L1 expression, enhancing the efficacy of anti-PD-1 therapy.
- Combined RT-MP and anti-PD-1 therapy demonstrated an ablative effect against MPE and cisplatin-resistant MPE models.
- The combination therapy also induced immunological memory.
Conclusions:
- RT-MPs are significant mediators of the radiation-induced bystander effect, primarily through ferroptosis-induced immunogenic cell death.
- RT-MPs reprogram the tumor microenvironment by polarizing TAMs and enhancing anti-PD-1 therapy efficacy.
- This study highlights the therapeutic potential of leveraging RT-MPs and immunotherapy for robust antitumor responses and immunological memory.
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