 Immunotherapy is a powerful method for treating cancer, harnessing the body's immune system to attack cancer cells. Despite recent advances in immunotherapy, however, clinical studies indicate that fewer than 20% of patients benefit from treatment. The ability to resist treatment, in fact, is what makes certain cancers, such as triple negative breast cancer or pancreatic cancer, so deadly. Now, researchers have identified a promising target for overcoming treatment resistance, the protein N-cor2. The researchers made their discovery by examining many organs grown from patients with treatment-resistant breast cancer. These organoids demonstrated abnormally high expression of N-cor2. Upon inspection, N-cor2 was found to repress the pro-inflammatory transcription factor IRF-1. This enabled cancer organoids to resist a form of cell death orchestrated by immune cells. Confirming this pathway was the discovery that N-cor2 expression correlated with therapy resistance in patients with breast cancer. In cohorts of nearly 1,600 patients who received surgery for breast cancer, higher levels of N-cor2 were linked to lower overall survival in those receiving systemic chemotherapy. Further experiments showed that N-cor2 inhibited IRF-1 and cell death through its interaction with a third role player in HDAC-3, an enzyme that regulates transcription in the cell nucleus. Eliminating HDAC-3 from the genome-abressed cancer cells that overexpressed N-cor2 effectively stopped them from eluding death at the hands of immune cells. Naturally, the team wondered whether they could introduce a protein that could disrupt the pro-cancer connection between N-cor2 and HDAC-3. That protein came in the form of D-cor2. Delivering the genetic instructions for fabricating D-cor2 using a viral vector proved successful. When injected into lab-grown and patient-derived tumors with high N-cor2 expression, the D-cor2 gene disabled their defenses and rendered them vulnerable to normal chemotherapy and immunotherapy. The researchers suggest that targeting the N-cor2 HDAC-3 connection could be one way to overcome treatment resistance and improve the outcomes of patients with cancer. They propose using gene therapy with D-cor2 to disrupt this complex and make tumor cells more sensitive to chemo and immunotherapies. Overall, this study highlights the importance of understanding the molecular mechanisms that underlie treatment resistance in cancer cells. And they demonstrate the power of patient-derived organoids as a tool for identifying and studying these mechanisms.