Targeting HIF-1α promotes ferroptosis and boosts antitumor immunity in MSS colorectal cancer

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Microsatellite stable colorectal cancer (MSS CRC) lacks effective therapies.
• Ferroptosis induction is a potential strategy, but resistance can emerge.
• Hypoxia pathways are implicated in treatment resistance.

Purpose of the Study:

• To investigate the role of hypoxia signaling in RSL3-induced ferroptosis resistance in MSS CRC.
• To evaluate the therapeutic potential of combining RSL3 with HIF-1α inhibition in MSS CRC.
• To assess the impact of combination therapy on the tumor immune microenvironment and anti-PD1 efficacy.

Main Methods:

• Cell culture and RSL3 treatment of MSS CRC cells.
• Single-cell RNA sequencing to identify resistance mechanisms.
• HIF-1α inhibition and overexpression studies.
• Chromatin immunoprecipitation assays.
• In vivo syngeneic mouse models (CT26 cells) with RSL3 and HIF-1α inhibitor combination therapy.
• Flow cytometry for immune cell infiltration analysis.

Main Results:

• RSL3 induced ferroptosis but encountered resistance in a subset of MSS CRC cells.
• Resistant cells exhibited aberrant activation of hypoxia pathways, driven by HIF-1α.
• HIF-1α inhibition restored RSL3 sensitivity; overexpression attenuated it.
• HIF-1α directly regulated P4HA1 expression, contributing to ferroptosis resistance.
• Combination therapy in vivo suppressed tumor growth, prevented metastasis, and increased CD8+ T cell and CD86+ macrophage infiltration.
• The combination therapy sensitized tumors to anti-PD1 treatment.

Conclusions:

• Targeting HIF-1α is a promising strategy to overcome RSL3 resistance in MSS CRC.
• Combining ferroptosis inducers with HIF-1α inhibitors can enhance antitumor immunity.
• This combination therapy may improve outcomes for MSS CRC patients, potentially synergizing with immunotherapy.