Our Goal is to sensitize human colorectal cancer (CRC) to the differentiation-inducing effects of retinoic acid (RA) agents by suppressing WNT signaling. Previously, we reported that the WNT and RA pathways are functionally linked, and in CRC, APC mutation generates a WNT:RA imbalance leading to incomplete differentiation and stem cell (SC) overpopulation. Hypothesis: Therapeutically inhibiting WNT signaling enhances the ability of retinoid agents to induce growth suppression and differentiation. We tested drug combinations of: (1) anti-WNT agents (Sulindac & Piroxicam) that produce anti-tumor activity in humans and animals harboring germline APC mutations, with (2) RA agents (All-trans-RA, 9-cis RA) and RA metabolism blocking agent (CYP26A1 inhibitors Liarozole and Talarozole), which inhibit proliferation and induce differentiation of CRC cell lines. Results: The combined effect of anti-WNT agents and RA drugs shows additive or synergistic responses in CRC cell lines compared to single agents. Drug combinations decrease the proportion of aldehyde dehydrogenase-positive SCs and increase neuroendocrine cell differentiation in CRC cells that show a synergistic response to treatment. NanoString profiling shows that therapeutically decreasing WNT signaling in CRC cells significantly changes the effect of RA signaling on gene expression. Treating human CRC organoid cultures and PDX mouse models with WNT:RA-based drug combinations led to greater anti-tumor activity as compared to individual agents. Conclusion: Inhibiting WNT signaling effectively sensitizes CRC cells to the anti-tumor effects of retinoids. These findings have important clinical significance for designing new drug combinations against CRC.

The recent study by Liu et al. provided compelling preclinical evidence that lenvatinib enhances the efficacy of combined radiotherapy and PD-L1 blockade by modulating both angiogenesis and antitumor immunity in lung adenocarcinoma. In this correspondence, I discuss the translational implications of these findings and highlight several challenges that should be addressed before clinical implementation. These include the molecular heterogeneity of lung adenocarcinoma, interpatient variability in the temporal dynamics of vascular normalization and immune activation, and the limitations of relying solely on PD-L1 expression for patient selection. I further emphasize the need for biomarker-driven and adaptive clinical trial designs incorporating functional imaging, circulating biomarkers, and immune monitoring to optimize treatment timing and identify patients most likely to benefit from this therapeutic strategy. These considerations may facilitate the successful translation of promising preclinical observations into precision radioimmunotherapy for lung adenocarcinoma.