LRRC15-radioimmunotheranostics: Targeting TGFβ-driven resistance in immune-excluded solid tumors.

e15133 Background: Leucine-Rich Repeat-Containing Protein 15 (LRRC15), a TGFβ-regulated antigen, is prominently expressed in mesenchymal-derived cancer cells and cancer-associated fibroblasts (CAFs) within aggressive, immune-excluded, and treatment-resistant tumors. In response to these challenges, we developed an LRRC15-targeted radioimmunotheranostic compound designed for molecularly specific, non-invasive imaging and therapy. To fully leverage this technology, our goal was to identify the genomic drivers of heterogeneous TGFβ-induced LRRC15 expression across various tumor microenvironments and to assess the diagnostic and therapeutic efficacy of LRRC15-radioimmunotheranostics. Methods: We utilized an integrated approach that combined high-throughput functional compound screening, single-cell RNA sequencing (scRNAseq), and small interfering RNA (siRNA) knockdown assays to identify genes influencing TGFβ-LRRC15 activity. The relationship of these genes with clinical outcomes was explored across various tumor cohorts. To facilitate clinical translation of LRRC15-targeted radiotheranostics, we investigated the therapeutic impact of [177Lu]-LRRC15 radioimmunotherapy (RIT) on TGFβ-LRRC15 activity through transcriptomic analyses in multiple murine tumor models at various post-treatment time points. Results: MMP2 , SPARC , TGFβR2 , and WNT5B were identified as key genes to the TGFβ-mediated upregulation of LRRC15. Their expression, especially within CAFs, correlated with patient responses to immunotherapy and the progression of aggressive tumors. [177Lu]-LRRC15 RIT effectively targeted TGFβ-driven LRRC15-positive CAFs and cancer cells, inhibiting tumor progression in murine models. Post-treatment transcriptomic analyses indicated a significant reduction in pro-tumorigenic signatures and disruption of the TGFβ-LRRC15 axis associated with immune resistance. Conclusions: Understanding the molecular pathways and genomic determinants that regulate biomarker dynamics is crucial for refining targeted diagnostic and therapeutic strategies. We identified TGFβR2 , MMP2 , SPARC , and WNT5B as pivotal drivers of LRRC15 upregulation in response to TGFβ signaling. Together, these markers, along with LRRC15, predict patient prognosis and response to immunotherapy in immune-excluded tumors. Our results highlight the potential of LRRC15-radiotheranostics to non-invasively detect, monitor, and target TGFβ-driven, immunotherapy-resistant tumors, demonstrating their substantial clinical and translational value.