On-demand responsive nanoplatform mediated targeting of CAFs and down-regulating mtROS-PYK2 signaling for antitumor...

Area of Science:

• Oncology
• Nanomedicine
• Biochemistry

Background:

• The desmoplastic tumor microenvironment (DTME) hinders nanoparticle delivery and efficacy.
• Mitochondrial reactive oxygen species (mtROS) overproduction drives tumor migration and metastasis.
• Targeting both the tumor microenvironment and intracellular pathways is crucial for effective cancer therapy.

Purpose of the Study:

• To develop a novel nanoparticle formulation (HPBC@TRP/NPs) for simultaneous targeting of the mtROS-PYK2 pathway and DTME remodeling.
• To investigate the combined therapeutic effects on inhibiting breast cancer growth and metastasis.

Main Methods:

• Synthesis of TPP-RSV prodrugs encapsulated in HPBC@TRP/NPs for mitochondrial targeting.
• Administration of Pirfenidone to remodel the DTME by inhibiting cancer-associated fibroblasts (CAFs), collagen, and hyaluronan.
• Evaluation of mtROS scavenging, PYK2 pathway modulation, apoptosis induction, and immune cell infiltration.

Main Results:

• HPBC@TRP/NPs effectively scavenged mtROS, reduced PYK2 expression, and activated apoptosis.
• Pirfenidone remodeled the DTME by decreasing interstitial fluid pressure (IFP) and TGF-β, while increasing cytotoxic T lymphocyte infiltration.
• The combination therapy demonstrated significant inhibition of tumor growth and metastasis.

Conclusions:

• The developed HPBC@TRP/NPs offer a dual-action strategy for breast cancer treatment.
• Targeting mtROS and remodeling the DTME represents a promising approach to overcome therapeutic barriers and inhibit metastasis.
• This combination therapy provides new insights into managing malignant breast cancer growth and spread.