Safe engineering of cancer-associated fibroblasts enhances checkpoint blockade immunotherapy

Abundant cancer-associated fibroblasts (CAFs) in highly fibrotic breast cancer constitute an immunosuppressive barrier for T cell activity and are closely related to the failure of immune checkpoint blockade therapy (ICB). Inspired by the similar antigen-processing capacity of CAFs to professional antigen-presenting cells (APCs), a turning foes to friends strategy is proposed by in situ engineering immune-suppressed CAFs into immune-activated APCs for improving response rates of ICB. To achieve safe and specific CAFs engineering in vivo, a thermochromic spatiotemporal photo-controlled gene expression nanosystem was developed by self-assembly of molten eutectic mixture, chitosan and fusion plasmid. After photoactivatable gene expression, CAFs could be engineered as APCs via co-stimulatory molecule (CD86) expression, which effectively induced activation and proliferation of antigen-specific CD8 + T cells. Meanwhile, engineered CAFs could also secrete PD-L1 trap protein in situ for ICB, avoiding potential autoimmune-like disorders caused by off-target effects of clinically applied PD-L1 antibody. The study demonstrated that the designed nanosystem could efficiently engineer CAFs, signif-icantly enhance the percentages of CD8+ T cells (4-folds), result in about 85% tumor inhibition rate and 83.3% survival rate at 60 days in highly fibrotic breast cancer, further inducing long-term immune memory effects and effectively inhibiting lung metastasis.

Automated summary

Abundant CAFs in highly fibrotic breast cancer act as an immunosuppressive barrier and are linked to the failure of ICB. To overcome this, a strategy to transform immune-suppressed CAFs into immune-activated APCs is proposed. A photo-controlled gene expression nanosystem is developed to engineer CAFs as APCs and induce activation and proliferation of CD8+ T cells.