PT_f‐SRiApt Targeting SCAF4‐POLR2A Interaction Suppresses Tumor Growth and Promotes Antitumor Immunity in Triple‐Negative Breast Cancer

Abstract The interaction between SCAF4 and RNA polymerase II (POLR2A) is crucial for proper mRNA termination, with its dysregulation leading to truncated mRNAs and nonfunctional proteins, impairing cellular growth. Despite its potential relevance, the role of this interaction in triple‐negative breast cancer (TNBC) remains unexplored due to the lack of effective molecular tools. To address this, we employed SRiApt, an aptamer generated through the recently established Blocker‐SELEX pipeline. Its biological stability is improved by phosphorothioate modifications to form PT_f‐SRiApt. Using this aptamer, the critical role of the SCAF4‐POLR2A interaction in driving TNBC tumor growth and immune regulation is uncovered. PT_f‐SRiApt effectively inhibits tumor growth and induces cell cycle arrest in TNBC cells with elevated SCAF4 and POLR2A expression. Additionally, PT_f‐SRiApt promotes premature mRNA termination, boosting antigen presentation and promoting T‐cell infiltration. Analysis of patient samples further confirmed the negative correlation between SCAF4‐POLR2A interaction and the effectiveness of immunotherapy, highlighting the potential of PT_f‐SRiApt in improving immune efficacy. Together, the work provides a powerful tool not only for dissecting previously “undruggable” protein‐protein interactions but also for enhancing tumor immunogenicity and reshaping the tumor microenvironment.