Preclinical Advances in Sensitizing ER-Positive Breast Cancer to Immunotherapy

Researchers at the Hospital del Mar Research Institute report a preclinical strategy that may sensitize ER-positive tumors to immune checkpoint blockade by combining estrogen receptor inhibition with a modified LCOR.

That finding contrasts with prior experience: ER-positive (luminal) tumors are typically immunologically cold, showing low antigen presentation and poor responses to checkpoint inhibitors. The team identified estrogen receptor–mediated sequestration of LCOR as a principal barrier—suppressing antigen-presentation programs and limiting lymphocyte infiltration—so reversing ER signaling restores immune visibility in the models tested.

The initial coverage summarized preclinical experiments linking combined ER blockade and LCOR modification to increased antigen presentation and tumor-infiltrating lymphocytes.

Methods described include a genetically modified LCOR construct engineered to resist ER binding, concurrent hormonal inhibitors, and readouts of antigen-presentation gene expression, TIL density, and response to checkpoint blockade. These mechanistic assays consistently supported immune sensitization across the models reported and provide a rationale for translation-focused evaluation.

Therapeutic concepts proposed pair estrogen receptor antagonists or degraders with LCOR-modified agents delivered via vector- or peptide-based modalities alongside immune checkpoint inhibitors. Trial design should prioritize timing—aligning hormonal blockade and LCOR delivery before checkpoint dosing—to maximize pharmacodynamic readouts and detect early biological effect.

Near-term biomarker candidates include LCOR expression or functional assays, antigen-presentation gene signatures, ER status and estrogen-signaling activity, TIL density, and PD-L1 or other inhibitory signals. A logical clinical sequence begins with phase I safety and delivery studies that integrate pharmacodynamic sampling and sentinel biomarker endpoints, followed by biomarker-driven expansion cohorts. The most actionable near-term outcome is demonstration of antigen-presentation induction in patient tumors after LCOR-directed intervention.

Key Takeaways:

• Modified LCOR with ER inhibition enables antigen presentation and immune recognition.
• ER-positive breast cancer patients with low antigen-presentation signatures become candidates for early-phase trials.
• Early-phase trials should prioritize integrated pharmacodynamic sampling and TIL endpoints to assess biological activity.