Research Projects

Colorectal cancer (CRC) is projected to affect over 3.2 million people by 2040, making it the third most common and second deadliest cancer globally [1]. Despite advances in treatment, immune checkpoint inhibitors (ICIs) show limited efficacy in CRC, especially in microsatellite stable (MSS) tumors, due in part to suppressed type I interferon (IFN) signaling [2–7]. Recent studies have highlighted the potential of “viral mimicry” approaches-using synthetic nucleic acids to activate innate immune sensors like retinoic acid inducible gene-I (RIG-I) as a means to restore IFN signaling and trigger robust antitumor responses [8,9]. Both my findings and those of others have shown that synthetic 5′-triphosphate RNA effectively activates RIG-I, initiating MAVS/IPS-1-dependent IFN responses. This not only induces tumor cell apoptosis but also enhances antigen presentation by DCs, priming CTLs [10–16]. Several early-phase clinical trials, including MK-4621 and CV8102 (NCT03291002, NCT03065023, NCT03739138) are evaluating RIG-I agonists in solid tumors, validating the translational potential of this approach. However, in CRC, the RIG-I gene (DDX58) and its adaptor MAVS are frequently mutated or downregulated, compromising antiviral immune signaling (Fig 1A–1E, TCGA). Additionally, IGF-1R-driven proteasomal degradation of RIG-I suppresses type I IFN responses [17]. Compounding this, the negative regulator of RIG-I-MAVS, Ubiquitin D (UBD/FAT10), is significantly upregulated in colon tumors (Fig 2A) and associated with recurrence and poor prognosis after 5-FU chemotherapy [18–20]. FAT10 promotes degradation of TRIM21, a factor known to enhance IFN-β production, reduce cancer stemness, and inhibit metastasis [21]. TRIM21 is also downregulated in CRC (Fig 2A-C, TCGA). Despite this, the role of the UBD–TRIM21–RIG-I axis in CRC remains poorly understood and has not been therapeutically explored. This study aims to uncover the molecular link between the RIG-I–NF-κB axis and type I IFNs in CRC following UBD silencing, with a focus on the plausible role of IFN regulatory factor 1 (IRF1) in reinstating immune surveillance. This project hypothesizes that dual targeting of CRC through a 5′ppp-siRNA-capable of both activating RIG-I and silencing UBD will restore type I IFN signaling and overcome immune evasion. The central aim is to design and evaluate a multifunctional immune-stimulating 5′ppp-siRNA nanoparticle complex for targeted cancer therapy. The proposed strategy tackles a critical bottleneck in PRR-based immunotherapy: efficient and targeted delivery. This dual-function 5′ppp-siRNA platform activates RIG-I while silencing its suppressor UBD, rewiring the CRC tumor microenvironment from immune-silent to immune-active via a self-amplifying IFN loop. It offers a novel, systemically deliverable immunotherapy with strong translational promise, while uncovering critical insights into the UBD–TRIM21–RIG-I axis driving immune escape in CRC.