Small-molecule PIK-93 modulates the tumor microenvironment to improve immune checkpoint blockade response.

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Immune checkpoint inhibitors (ICIs) targeting PD-L1 are key treatments for advanced non-small cell lung cancer (NSCLC).
• Treatment resistance in NSCLC is often linked to an unfavorable tumor microenvironment (TME) and limited antibody penetration.
• There is a need for strategies to enhance ICI efficacy by modulating the TME.

Purpose of the Study:

• To identify small-molecule drugs capable of modulating the TME to improve ICI treatment outcomes in NSCLC.
• To investigate the mechanism by which PIK-93 affects PD-L1 expression and macrophage function.
• To evaluate the combined efficacy of PIK-93 and anti-PD-L1 antibodies in preclinical NSCLC models.

Main Methods:

• Utilized a cell-based global protein stability (GPS) screening system to identify PD-L1 modulating small molecules.
• Investigated PIK-93's mechanism of action, including its effect on PD-L1 ubiquitination and interaction with Cullin-4A.
• Assessed the impact of PIK-93 on M1 macrophage function and antitumor cytotoxicity in vitro.
• Evaluated the combined therapeutic effect of PIK-93 and anti-PD-L1 antibodies in syngeneic and xenograft mouse models of NSCLC.

Main Results:

• Identified PIK-93 as a novel small molecule that reduces PD-L1 levels on M1 macrophages by enhancing PD-L1 ubiquitination.
• PIK-93 treatment increased M1 macrophage antitumor cytotoxicity.
• Combination therapy with PIK-93 and anti-PD-L1 antibodies enhanced T cell activation and tumor-infiltrating lymphocyte (TIL) recruitment.
• Combined treatment significantly inhibited tumor growth in preclinical NSCLC models.

Conclusions:

• PIK-93 effectively modulates PD-L1 levels and enhances the anti-tumor activity of M1 macrophages.
• Combining PIK-93 with anti-PD-L1 antibodies creates a more favorable TME, overcoming resistance to ICI therapy.
• This combination strategy shows significant promise for improving PD-1/PD-L1 blockade immunotherapy in NSCLC.