Synergistic targeting of MCL1 and caspases for enhanced anti-tumor immunity in breast cancer
Year: 2025
Type: preprint
Abstract: Breast cancer remains largely unresponsive to immunotherapy due to its immunologically “cold” nature, marked by low cytolytic activity and a paucity of neoantigens. To overcome this, we developed a novel therapeutic approach to activate the cGAS-STING pathway, a critical mediator of the type I interferon response essential for effective anti-tumor immunity. We demonstrate that combined inhibition of MCL1 and caspases robustly triggers a type I IFN response in breast cancer cells, effectively remodeling the tumor microenvironment by increasing immune cell infiltration and enhancing antigen presentation. In immunocompetent syngeneic mouse models, this combination therapy significantly suppressed tumor growth, an effect that was reversed upon blockade of the IFN signaling axis. Mechanistically, our findings reveal that co-targeting MCL1 and caspases reprograms the tumor microenvironment enhancing immune surveillance. Given the established safety profiles of both drug classes, this strategy offers a promising and rapidly deployable approach to sensitize breast tumors to immunotherapy.
Authors: Jae Kyo Yi, Ji-Sun Lee, Pilhan Kim, Leslie M. Shaw, Alexander Spektor
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4415052665