In Situ Engineering of Tumor Cells as Self-Sustaining cDC1 Programming Factories for Effective Cancer Immunotherapy

Area of Science:

• Immunology
• Biotechnology
• Cancer Research

Background:

• Conventional type 1 dendritic cells (cDC1s) are vital for antitumor immunity but are often insufficient and dysfunctional within the tumor microenvironment.
• Tumor-infiltrating cDC1s are critical for initiating and regulating effective anti-cancer immune responses.
• Overcoming cDC1 limitations in tumors is a key challenge in cancer immunotherapy.

Purpose of the Study:

• To engineer tumor-derived extracellular vesicles (EVs) to reprogram tumor cells into local factories for cDC1 recruitment and activation.
• To enhance the anti-tumor immune response by overcoming cDC1 deficiency and dysfunction within the tumor microenvironment.
• To develop a novel therapeutic strategy for cancer immunotherapy using engineered EVs.

Main Methods:

• Engineered tumor-derived EVs (AS16-EL@MPLA/p-FX) loaded with plasmids encoding XCL1 and FLT3L.
• Utilized EV properties for tumor-selective accumulation and cellular internalization.
• Incorporated MPLA for TLR4-mediated cDC1 activation and AS16 peptide for disrupting VEGF-NRP1 interaction to prevent cDC1 exhaustion.

Main Results:

• Engineered EVs demonstrated enhanced tumor targeting and efficient uptake by tumor cells.
• Reprogrammed tumor cells secreted XCL1 and FLT3L, effectively recruiting and differentiating cDC1s.
• MPLA activated recruited cDC1s, while AS16 peptide prevented cDC1 exhaustion, leading to significant tumor growth inhibition.
• The treatment induced a robust immune memory response, preventing metastasis and recurrence.

Conclusions:

• Engineered EVs can reprogram tumor cells into in situ cDC1 programming and activation centers.
• This strategy overcomes limitations of cDC1 infiltration and function in the tumor microenvironment.
• The AS16-EL@MPLA/p-FX approach shows significant potential for enhancing cancer immunotherapy and establishing long-term anti-tumor immunity.