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Updated: Mar 4, 2026
Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells
Published on: March 7, 2025
Dynamic reprogramming of the tumor immune network via multicycle checkpoint degradation for cancer immunotherapy
Tao Shi1, Yuanyuan Wu2, Yiran Cai1
1Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
Abstract:
The efficacy of immune checkpoint blockade is often limited by intrinsic immunosuppressive networks within the tumor immune microenvironment (TIME). Despite progress in cancer treatment, current extracellular targeted protein degradation approaches often overlook the multicellular distribution and crosstalk of immune checkpoints. Here we reported a Receptor-mediated Endolysosomal recYcling Chimera (RECYC) platform. RECYC employs a CI-M6PR-targeting aptamer that remains stable across late endosomal pH and a protein-binding peptide with moderate affinity and pH responsiveness, which together drive recycling and sustained checkpoint clearance. In ex vivo co-culture and in vivo murine models, RECYC efficiently eliminated programmed death-ligand 1 (PD-L1) expression from both tumor cells and tumor-associated myeloid cells (macrophages, neutrophils and dendritic cells). By converting an immunosuppressive TIME to an immunostimulatory state, RECYC remodeled the tumor-immune network in an anti-tumor direction, thereby enhancing CD8+ T cell response and repolarizing immunosuppressive myeloid cells. Moreover, in both immune-cold and immune-hot murine cancer models, RECYC demonstrated superior anti-tumor effect compared to PD-L1 blockade treatment. Collectively, we propose an effective strategy to induce recycling and broad checkpoint clearance in the TIME, which in turn reprograms the multicellular tumor-immune network to achieve durable immunotherapy responses.
Insights
A novel RECYC platform clears immune checkpoints like PD-L1 on tumor and myeloid cells. This approach converts the immunosuppressive tumor microenvironment (TIME) to an immunostimulatory state, enhancing anti-tumor immunity and improving immunotherapy responses.
Area of Science:
- Immunology
- Cancer Biology
- Biotechnology
Background:
- Immune checkpoint blockade efficacy is limited by the immunosuppressive tumor immune microenvironment (TIME).
- Current extracellular targeted protein degradation methods do not fully address the complexity of immune checkpoints in the TIME.
- Multicellular distribution and crosstalk of immune checkpoints pose challenges for cancer treatment.
Purpose of the Study:
- To develop a novel platform for sustained immune checkpoint clearance within the TIME.
- To investigate the potential of RECYC in reprogramming the tumor-immune network.
- To enhance anti-tumor immunity and improve immunotherapy outcomes.
Main Methods:
- Development of a Receptor-mediated Endolysosomal recYcling Chimera (RECYC) platform.
- Utilizing a CI-M6PR-targeting aptamer and a pH-responsive protein-binding peptide for checkpoint clearance.
- Testing RECYC in ex vivo co-culture and in vivo murine models, including immune-cold and immune-hot cancer models.
Main Results:
- RECYC efficiently eliminated programmed death-ligand 1 (PD-L1) expression on tumor cells and myeloid cells (macrophages, neutrophils, dendritic cells).
- RECYC converted the TIME from immunosuppressive to immunostimulatory, enhancing CD8+ T cell responses.
- RECYC demonstrated superior anti-tumor effects compared to PD-L1 blockade in murine cancer models.
Conclusions:
- The RECYC platform offers an effective strategy for recycling and broad immune checkpoint clearance in the TIME.
- RECYC reprograms the multicellular tumor-immune network, leading to durable immunotherapy responses.
- This approach holds promise for overcoming limitations of current cancer immunotherapies.
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