Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• PD-1 inhibitors show clinical benefit but require synergizers for broader efficacy.
• Tumor-associated macrophages (TAMs), typically M2-polarized, suppress anti-tumor T-cell responses.
• Reprogramming TAMs to an M1 phenotype is a promising anti-cancer strategy.

Purpose of the Study:

• To identify compounds that can reverse M2 TAM polarization.
• To investigate the mechanism of Carfilzomib in modulating TAMs.
• To evaluate the synergistic effect of Carfilzomib and PD-1 inhibitors in cancer therapy.

Main Methods:

• High-throughput screening to identify TAM-modulating agents.
• In vitro assays assessing M2 macrophage polarization, phagocytosis, and antigen presentation.
• In vivo studies using a transgenic mouse model of autochthonous lung cancer.
• Combination therapy experiments with Carfilzomib and PD-1 antibodies.

Main Results:

• Carfilzomib effectively induced M1 cytokine expression, phagocytosis, and antigen presentation in M2 macrophages.
• Carfilzomib activated the unfolded protein response (UPR) pathway, specifically IRE1α-TRAF2-NF-κB signaling.
• In vivo, Carfilzomib reprogrammed TAMs, reduced tumor burden, and synergized with PD-1 blockade for near-complete tumor regression.

Conclusions:

• Carfilzomib is a potent inducer of M1 macrophage polarization via the UPR pathway.
• Carfilzomib demonstrates significant anti-tumor activity and synergizes with PD-1 inhibitors.
• This combination holds potential for immediate clinical application in solid tumor treatment.