Chen, @rweichselbaum et al. @UChicago discover that YTHDF2 in #DendriticCells negatively regulates antitumor immunity of #radiotherapy. The SPI1–YTHDF2–Notch signaling–MHC-I axis orchestrates the antigen cross-presentation function of dendritic cells. https://t.co/Fm1GBEE3Im

@rweichselbaum @UCCancerCenter @UChicagoMed @UChicagoRadonc @LudwigCancer

6/ Takeaway: RT induces YTHDF2 in DCs, which suppresses antigen presentation and limits systemic antitumor immunity. Targeting YTHDF2 is a promising strategy to enhance RT + immune therapy and improve metastatic control. 🔗 https://t.co/qdkYg5agQJ

5/ Therapeutic angle: DC vaccines engineered to inhibit YTHDF2 significantly improve the immune efficacy of RT in both mouse models and human DC–T cell co-culture assays.

4/ Deleting Ythdf2 in DCs: • Enhances RT-induced local tumor control • Strengthens CD8⁺ T cell priming • Reduces metastatic spread

3/ Mechanism: RT → ↑ SPI1 → ↑ YTHDF2 in DCs YTHDF2 then degrades m⁶A-modified transcripts that support Notch signaling, which is required for MHC-I cross-presentation.

2/ In patient samples from the COSINR trial (SBRT + ICB for metastatic NSCLC), RT selectively increased YTHDF2 in DCs — especially in patients who later progressed. This effect was not seen in responders.

1/ New paper 🚨 Radiotherapy (RT) can activate antitumor immunity — but it can also impact metastatic spread in ways we don’t fully understand. In our new study, we identify a radiation-induced immune checkpoint in dendritic cells (DCs) that limits CD8⁺ T cell priming.

8/ Summary: Radiation doesn’t “spread cancer.” But biology is complex — and embracing that complexity helps us make SBRT even more effective. @rweichselbaum @AndrasPiffko Hua Laura Liang @SeanPitroda 📄 Authors’ View now in @IJROBP @NaturePortfolio @UChicago @UChicagoMed

7/ Where we go next 👇 💥 Deliver fully ablative doses when safe 🧫 Track circulating AREG & EGFR⁺ monocytes as biomarkers 🧬 Test AREG/EGFR or CD47 blockade to prevent dormancy escape

6/ We’re not arguing against SBRT — far from it. SBRT remains one of the most powerful curative tools in oncology. But understanding radiation’s dual systemic effects opens new opportunities to refine therapy. #PrecisionOncology #RadOnc

5/ Clinically, patients with the highest post-SBRT AREG & CD14⁺CD33⁺pEGFR⁺ monocytes had worse outcomes (COSINR trial). ⚠️ Implication: dose matters — incomplete local control can trigger systemic effects.

4/ AREG didn’t make cancer spread. It reprogrammed circulating monocytes, creating an immune environment that allowed existing lesions to grow faster. This distinction matters for how we interpret progression after SBRT.

3/ Mechanism: incomplete tumor ablation → ↑ amphiregulin (AREG) → EGFR activation in monocytes → immunosuppression → dormant micrometastases “wake up.” 🧬 This is dormancy escape, not new metastatic seeding.

2/ 🚫 We did NOT find that radiation causes new metastases. ✅ High-dose RT suppressed tumor cell dissemination. The nuance: suboptimally irradiated tumors can release systemic signals that accelerate growth of pre-existing metastases.

1/ Our Nature paper on radiation-induced AREG sparked discussion - and some misinterpretation ( https://t.co/ZPfEqgqXcZ). We clarify key points in our new Authors’ View in the Red Journal (@IJROBP). 🧵 Here’s what we actually found — and what we didn’t: https://t.co/3qJlkH8jOX

14/14 @AndrasPiffko @rweichselbaum @UChicagoRadonc @UCCancerCenter @UChicagoMed @LudwigCancer

13/14 🎯 BOTTOM LINE: AREG represents an ACTIONABLE pathway—not just mechanistic insight. By identifying high-risk patients and intervening strategically, we can preserve SBRT's benefits while mitigating unintended effects. Full text: [ https://t.co/Nh3q61YNe2]

12/14 🚀 FUTURE DIRECTIONS: We need trials that: - Integrate real-time biomarker assessment - Allow biomarker-guided interventions - Test AREG/EGFR blockade in high-risk patients - Don't mandate stopping at first progression The biology demands dynamic trial design.

11/14 📈 SERIAL MONITORING: For patients who develop INDUCED AREG or other tumor-promoting factors: These proteins can be identified during treatment and targeted with TAILORED INTERVENTIONS in subsequent therapies. Precision medicine in action.