The most effective weapon against cancer is arguably the patient’s own immune system. As immune cells continuously patrol through the body and are thus capable of eliminating not only the tumor at its primary site but also cancer cells that have already spread to other parts of the body. Furthermore, a full immune response also prevents tumor recurrence in the long term thanks to the formation of memory immune cells that can easily be reactivated should a tumor relapse. Accordingly, development of cancer vaccines that train the immune system to mount an effective response against a tumor is of great importance. The immune system distinguishes between self and foreign by recognizing specific structures called antigens, which makes it paramount to identify tumor-associated neoantigens that are not present in normal cells. Currently, most cancer vaccine strategies focus on neoantigens derived from cancer-specific mutations, small protein alterations that can nonetheless elicit immune recognition and tumor cell destruction. However, these vaccines require personalized design for each patient, making them costly, time-intensive, and not broadly applicable to a large set of patients. Furthermore, many tumors exhibit a low mutational burden, reducing their chances to express targetable neoantigens in the first place. Importantly, RNA processing is frequently altered in cancer, either due to mutations or differential expression of RNA-binding proteins. Because RNA processing occurs upstream of protein production, even minor disruptions can lead to widespread transcriptomic changes, resulting in the generation of numerous neoantigens. Despite this, no cancer vaccine targeting these antigens has thus far been developed. We recently discovered that depletion of a key RNA binding protein triggers widespread RNA processing defects that have the potential to create a vast array of neoantigens. Intriguingly, we noticed that the vast majority of the resulting aberrant RNA transcripts are specifically sequestered in the nucleus of cells. Since translation of RNAs into proteins occurs in the cytoplasm, nuclear retention of altered RNAs likely represents a novel mechanism by which tumors evade immune detection. In this proposal, we aim to uncover how incompletely processed RNAs are retained in the nucleus and identify strategies to override this retention. We will screen a library of 4711 FDA-approved drugs to identify compounds that interfere with nuclear RNA retention and analyze in a complementary approach a set of candidate proteins directly for their role in sequestering RNAs inside the nucleus. Understanding and ultimately targeting this process holds the potential to establish a new class of anti-cancer therapies that can force tumors to reveal their hidden neoantigens, rendering them vulnerable to immune attack.