Tumor targeting dendritic nanocarrier with immunogenic cell death inducing and TIGIT blockade for synergistic chemo-immunotherapy against TNBC

J Nanobiotechnology. 2025 Dec 7;23(1):759. doi: 10.1186/s12951-025-03875-0.

Abstract

The clinical therapeutic effect of immune-checkpoint blockade (ICB) on triple-negative breast cancer (TNBC) is limited due to low tumor immunogenicity and tumor immunosuppressive microenvironment. Combination therapies of chemotherapy and ICB have been confirmed efficacious. Herein, poly(L-lysine) dendrimer (PLLD) nanosphere (PR-T@PLLD) integrating chemotherapeutic drug paclitaxel (PTX), natural anti-tumor compound Rubioncolin C (RC) and TIGIT/PVR blocking peptide DTBP-3 is constructed for chemo-immunotherapy of anti-PD-1 resistant tumor. The PEGylation and DTBP-3 modification endow PR-T@PLLD with prolonged blood circulation, enhanced tumor penetration and improved internalization. In the acidic environment of lysosomes, PR-T@PLLD disassembles and releases PTX, RC and DTBP-PLLD. The cell death induced by PTX is significantly enhanced through synergy with RC. RC collaborated PTX also triggers robust immunogenic cell death that efficiently increases tumor infiltration of cytotoxic T lymphocytes (CTLs). Additionally, the released DTBP-PLLD inhibits the exhaustion of CTLs via directly binding to TIGIT and blocking the interaction of TIGIT with its ligand PVR. Thus, PR-T@PLLD arouses a conspicuous anti-tumor immune response via increasing income and reducing expenditure of CTLs. Moreover, PR-T@PLLD reduces the recruitment of immunosuppressive cells in tumor. PR-T@PLLD also inhibits tumor metastasis through evoking immune memory response and inhibiting epithelial-mesenchymal transition and extracellular matrix degradation. In general, PR-T@PLLD is a promising nanoplatform realizing synergistic enhancement of chemo-immunotherapy against anti-PD-1 resistant TNBC.

Keywords: Chemo-immunotherapy; Immunogenic cell death; Poly(L-lysine) dendrimer; TIGIT/PVR blockade; Tumor immunosuppressive microenvironment.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Dendrimers / chemistry
  • Drug Carriers* / chemistry
  • Drug Synergism
  • Female
  • Humans
  • Immunogenic Cell Death* / drug effects
  • Immunotherapy* / methods
  • Mice
  • Mice, Inbred BALB C
  • Nanoparticles* / chemistry
  • Paclitaxel / chemistry
  • Paclitaxel / pharmacology
  • Receptors, Immunologic* / antagonists & inhibitors
  • Receptors, Immunologic* / metabolism
  • T-Lymphocytes, Cytotoxic
  • Triple Negative Breast Neoplasms* / drug therapy
  • Triple Negative Breast Neoplasms* / immunology
  • Triple Negative Breast Neoplasms* / therapy

Substances

  • Receptors, Immunologic
  • TIGIT protein, human
  • Paclitaxel
  • Dendrimers
  • Antineoplastic Agents
  • Drug Carriers