When we began studying RNA-binding proteins (RBPs) nearly twenty years ago, we had no idea where this journey would take us. Back then, RBPs were a niche topic, interesting mainly to a small community of RNA biologists. Few would have imagined that they might one day help explain why ovarian cancers evade immune control. For a long time, RBPs were also largely considered undruggable.
Our entry into ovarian cancer started with a purely mechanistic question: how much do alternative polyadenylation and 3′UTR shortening really matter in tumors, beyond artificial translation systems? Early on, we noticed that the RBPs we had studied for years appeared only in a subset of high-grade serous carcinomas (HGSCs). This was both frustrating and intriguing. Molecular subtypes had already been described — proliferative, immune responsive, differentiated, mesenchymal — but patient-level subtype annotations were never released. Public datasets showed the clusters, but not which tumor belonged where. Re-clustering everything ourselves was not an option. We were not trying to redefine subtypes; we simply wanted to know whether our RBPs followed the existing ones. It felt like having a map with all coordinates missing.
Eventually, we did the work ourselves. Using transcriptomic signatures, we assigned subtype identities across large RNA-seq and microarray datasets. The result was striking. Across cohorts, platforms, and studies, RBPs consistently mapped to the same group: the C5 subtype — proliferative, aggressive, and immunologically cold. Even more surprisingly, a conserved set of eight RBPs appeared in every dataset we examined: LIN28B, MSI1, IGF2BP1, IGF2BP3, DDX25, ELAVL3, MKRN3, and MEX3A. All were oncofetal, all associated with C5, and all linked to stemness-like phenotypes that are notoriously difficult to treat. What began as a technical curiosity revealed a much broader biological pattern.
Figure. Inhibition of RNA-binding proteins enhances immunotherapy in ovarian cancer.
To explore their functional relevance, we performed a targeted screen across multiple HGSC cell lines. Several RBPs affected proliferation and invasion. However, the most unexpected finding was their role in immune evasion. IGF2BP1 stood out with a particularly strong immunological phenotype. It increased PD-L1 expression while simultaneously reducing MHC class I levels — but only partially. Enough to dampen T-cell activation, yet not enough to trigger NK-cell surveillance. A remarkably precise post-transcriptional tuning of immune invisibility.
Dissecting these mechanisms took years and followed the rapid evolution of available technologies, from multiplex imaging to single-cell RNA-seq and m⁶A profiling. The emergence of IGF2BP1 inhibitors ultimately added a translational dimension that reshaped the project once again. The paper now integrates data generated over seven years.
Progress was driven not only by persistence, but also by collaboration. A scientific exchange between Halle and Oxford, initiated by Stephan Feller, connected us with Ahmed Ahmed and, through him, with Iain McNeish. Access to a syngeneic mouse model provided the in vivo context necessary to test our hypotheses and proved essential for the final study. This work also highlights what modern translational cancer research requires: close collaboration between basic scientists, clinicians, and pharmacists. Only by connecting molecular mechanisms with patient models and therapeutic strategies can discoveries like this move toward the clinic.
We are realistic about the therapeutic implications. RBPs — including IGF2BP1 — are unlikely to cure ovarian cancer on their own. However, they may act as sensitizers. Our data suggest that targeting RBPs could help unlock responses to checkpoint inhibition in tumors that are otherwise immunologically silent. Their oncofetal expression pattern makes them particularly attractive for tumor-selective intervention with limited side effects. HGSC will almost certainly require combination therapies, and RBPs may help tip the balance.
Taken together, our findings position RNA-binding proteins as key regulators of immune visibility in HGSC and as emerging therapeutic targets. Beyond ovarian cancer, similar post-transcriptional circuits may contribute to immune evasion in other immunologically cold tumors, opening potential avenues for combination immunotherapies across cancer types.