Metformin Mediated PD‐L1 Downregulation in Combination with Photodynamic‐Immunotherapy for Treatment of Breast Cancer

Abstract

Intelligent nanomaterials open up new avenues for realizing safer and more effective combination immunotherapy. Herein, a kind of simple enzymatically cleavable self‐delivery nanoparticles (MA‐pepA‐Ce6 NPs) is developed by conjugating acidic‐sensitive small‐molecule programmed cell death ligand 1 (PD‐L1) inhibitor (Metformin, MET) with photosensitizer (chlorin e6, Ce6) through matrix metalloproteinase‐2 (MMP‐2) cleavable peptide (GPLGVRGDK, pepA). Noticeably, these self‐delivery peptide‐based NPs can circumvent the controversial biosafety facing nanomaterials. Moreover, MA‐pepA‐Ce6 NPs are degraded by overexpressed MMP‐2 in tumor microenvironment (TME) and expose the VRGDK‐Ce6. The exposed VRGDK‐Ce6 shows superior targeting ability towards integrin αvβ3 receptor, ensuring sufficient accumulation and laser‐activated robust antitumor immune effects. Remarkably, the released MET in tumor microenvironment hampers the PD‐L1 expression and augments the antitumor immune response elicited by photodynamics therapy (PDT), thus significantly improving therapeutic outcomes. Overall, this study offers a potential appealing paradigm of synergistic PDT‐triggered immunotherapy by revealing MET‐mediated PD‐L1 downregulation to achieve tumor eradication.

Light-controllable charge-reversal nanoparticles with polyinosinic-polycytidylic acid for enhancing immunotherapy of triple negative breast cancer

“…PDT was considered as a feasible strategy to generate immunogenic cell death (ICD). PDT-triggered immunotherapy with immune checkpoint blockade has offered a potential appealing paradigm to eradicate tumors 30 . ICD was featured by surface exposure of calreticulin (CRT), cytosol release of high mobility group box 1 (HMGB1) and extracellular release of adenosine triphosphate (ATP) 31 .…”

New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway

“…Additionally, metformin can downregulate PD-L1 to increase sensitivity to immunotherapy. Overall, MA-pepA-Ce6 NPs can increase the effectiveness of PDT and ICIs in suppressing the growth of 4T1 mouse breast cancer cells in vitro and in vivo [116]. 4.6.3.…”

Supramolecular cancer photoimmunotherapy based on precise peptide self-assembly design

“…2D). 62 Matrix metalloproteinase-2 (MMP-2) is high-expressed in a variety of tumors and plays a key role in the invasion and metastasis of tumors, which is widely used in designing adaptive materials. 37 The formed MA-pepA-Ce6 NPs are degraded by cleaving GPLGVRGDK at a specific site between glycine (G) and valine (V) by highly-expressed MMP-2 and exposing the VRGDK-Ce6 and MET-GPLG.…”