Background: Accurate glioma subregion delineation is important for radiotherapy planning and longitudinal monitoring, but manual contour correction is time-consuming. Models such as nnU-Net may generalize imperfectly and lack clinician-directed text correction. Purpose: We investigated adapting a three-dimensional (3D) vision-language foundation model for text-guided brain tumor segmentation refinement. Methods: We developed a lightweight VoxTell-based framework. Pretrained VoxTell generated initial masks. Oracle prompts derived from segmentation errors encoded target, action, location, imaging evidence, edit size, and preservation constraints. Frozen Qwen/VoxTell prompt embeddings were injected through trainable projections into its multiscale decoder conditioning; other weights remained frozen. Training, validation, and testing used 901, 100, and 250 BraTS-GLI cases. Cross-dataset transfer was evaluated on 100 meningioma, metastasis, pediatric tumor, and UPENN-GBM cases. Results: On the internal test set using post-contrast T1-weighted input, correct instructions improved subregion Dice similarity coefficient (DSC; enhancing tumor, edema, and necrotic/non-enhancing core) from 0.774±0.158 to 0.796±0.137. They outperformed blank prompts (0.762±0.155; Holm-adjusted p<0.001, d_z=0.71) and contradictory prompts (0.770±0.163; p<0.001, d_z=0.48). In cross-dataset testing, correct instructions improved DSC from 0.527±0.287 to 0.550±0.278 and outperformed contradictory instructions (0.504±0.275; p<0.001, d_z=0.43). Conclusion: A 3D vision-language foundation model can perform instruction-guided refinement of glioma subregion segmentations. Sensitivity to correct, blank, and contradictory prompts suggests text-dependent contour editing rather than nonspecific post-processing, supporting further evaluation as a clinician-in-the-loop tool.

For decades, microRNAs (miRNAs) have been canonically viewed as post-transcriptional repressors. We discovered extensive binding of microRNAs to chromatin-associated RNAs (caRNAs) and uncovered an N 6 -methyladenosine (m 6 A)-dependent transcriptional activation mechanism of microRNAs. We show that m 6 A-binding proteins FXR1/2 anchor AGO1/2 at m 6 A-marked caRNAs, where AAGUGC-seed microRNAs function as guide RNAs to direct AGO positioning. This dual anchoring stabilizes the AGO-microRNA/FXR-m 6 A complex at specific loci, which in turn recruits the ATP-dependent chromatin remodeler SMARCA4 (BRG1) to promote local chromatin opening and TET1 for DNA demethylation, respectively. Together, these coordinated activities establish a transcriptionally permissive chromatin environment, enhancing accessibility and transcription across hundreds of genes in diverse cell types. Beyond the AAGUGC-seed family, additional microRNAs and siRNAs also enhance transcription, suggesting that caRNA binding and transcriptional activation may represent a broader property of small RNAs.

Radiotherapy (RT), while pivotal in cancer control, may paradoxically promote metastasis through systemic effects. Emerging evidence implicates RT-induced growth factors and immune modulation-especially via amphiregulin-epidermal growth factor receptor (EGFR) signaling-in facilitating metastatic outgrowth at distant sites. This effect underscores the need to refine RT strategies, identify high-risk patients, and explore therapeutic combinations targeting myeloid cells and EGFR pathways to mitigate pro-metastatic consequences and optimize outcomes in the immunotherapy era.

The anti-tumour effect of radiotherapy beyond the treatment field-the abscopal effect-has garnered much interest1. However, the potentially deleterious effect of radiation in promoting metastasis is less well studied. Here we show that radiotherapy induces the expression of the EGFR ligand amphiregulin in tumour cells, which reprogrammes EGFR-expressing myeloid cells toward an immunosuppressive phenotype and reduces phagocytosis. This stimulates distant metastasis growth in human patients and in pre-clinical mouse tumour models. The inhibition of these tumour-promoting factors induced by radiotherapy may represent a novel therapeutic strategy to improve patient outcomes.

The oligometastatic state, characterized by limited metastatic dissemination, challenges the view that metastatic cancer is widespread and incurable. Evidence suggests that select patients with restricted metastases may achieve long-term disease control or even cure with local therapies, such as surgery or stereotactic body radiotherapy (SBRT). Radiotherapy induces complex, dose-dependent effects on the tumor microenvironment, including the release of immunogenic cytokines and damage-associated molecular patterns, enhanced antigen presentation on cancer cells, and infiltration of effector T cells, NK cells, and macrophages. These immunomodulatory effects provide a compelling basis for combining SBRT with immune checkpoint inhibitors to enhance local and systemic antitumor immunity. Several prospective phase I-II trials have investigated various combinations of radiotherapy and immunotherapy in the oligometastatic setting, demonstrating acceptable safety profiles and promising efficacy signals. However, clinical outcomes reported with combined radioimmunotherapy have largely been mixed, which likely reflects variability in SBRT dosing, sequencing of therapy, type of immunotherapy, patient selection, and tumor characteristics. Notably, studies employing comprehensive ablative SBRT to all metastatic sites seem to more consistently demonstrate superior outcomes over standard-of-care systemic therapy, as opposed to sub-ablative or single-lesion irradiation. Advancing the therapeutic paradigm of radioimmunotherapy combinations for oligometastatic disease requires improved patient selection based on clinical, molecular, or radiographic features; rigorous optimization of radiotherapy dose fractionation to maximize immune priming while minimizing toxicities; and rational integration with novel immunotherapeutic agents that target complementary immune pathways.

Aneuploidy, a hallmark of cancer characterized by chromosome imbalances, drives tumorigenesis and facilitates cancer immune evasion. While high tumor aneuploidy is linked to immune checkpoint blockade (ICB) resistance and poor prognosis, evidence suggests that this resistance can be overcome through treatment intensification, for example, with the addition of ablative radiotherapy to ICB. In this Perspective, we argue that the predictive value of aneuploidy complements established biomarkers, such as tumor mutational burden (TMB) or programmed death ligand 1 (PD-L1) expression. We review contemporary methods for quantifying aneuploidy, explore novel approaches that target mitotic vulnerabilities in aneuploid tumors and highlight potential areas where aneuploidy-based stratification could be incorporated into ICB-based treatment paradigms across early-stage, locally advanced and metastatic cancers. Prospective trials incorporating aneuploidy-based stratification will be essential to validate its role in personalized cancer therapy.

Purpose Metastasis-directed therapy for oligometastatic renal cell carcinoma (RCC) with stereotactic body radiation therapy (SBRT) has been shown to improve progression-free survival (PFS) and delay time to systemic therapy. Here, we present long-term follow-up of a prospective trial. Methods and Materials Patients with oligometastatic or recurrent RCC (1-5 lesions, with no therapies in prior month) were enrolled on a pilot study (NCT02542202). SBRT was delivered to all sites (preferred regimen of 50 Gy in 5 fractions). The primary endpoint was the rate of grade 4+ adverse events, and secondary endpoints included local failure, distant progression, and PFS. Exploratory endpoints included time to subsequent systemic therapy and time to subsequent metastasis-directed therapy. Results Fifteen patients (all with resected primary tumors, 40% prior systemic therapy, 47% International Metastatic RCC (Renal Cell Carcinoma) Database Consortium intermediate risk) received SBRT to 23 lesions (median, 1; range, 1-4; median BED10 (Biologically Effective Dose, α/β=10) of 100 Gy; 43% lung, 35% abdomen, 17% bone, 4% head and neck). The trial was closed early due to slow accrual. At a median follow-up of 4.8 years, there were no grade 3+ adverse events (AEs) and no late grade 2+ AEs. Five (33%) patients experienced 7 acute grade 2 AEs. Two-year PFS was 46% (90% CI, 24%-65%). At 5 years, cumulative incidence of local failure was 6.7% (90% CI, 0.8%-22%), distant progression was 85% (90% CI, 60%-95%), subsequent systemic therapy was 54% (90% CI, 31%-73%), and subsequent metastasis-directed therapy was 52% (90% CI, 22%-76%). The median time to subsequent systemic therapy was 2.6 years. Conclusions Multisite SBRT in oligometastatic RCC offers excellent local control with a low risk of severe late toxicity. This study supports an approach to treat limited metastatic disease with SBRT to delay additional systemic therapy. A subset of patients may benefit from additional, repeated ablative local interventions.

Could a common cancer treatment be quietly fueling the spread of tumors it’s meant to suppress?

The annual ImmunoRad Conference has established itself as a recurrent occasion to explore the possibility of combining radiation therapy (RT) and immunotherapy (IT) for clinical cancer management. Bringing together a number of preclinical and clinical leaders in the fields of radiation oncology, immuno-oncology and IT, this annual event fosters indeed essential conversations and fruitful exchanges on how to address existing challenges to expand the therapeutic value of RT-IT combinations. The 8th edition of the ImmunoRad Conference, which has been held in October 2024 at the Weill Cornell Medical College of New York City, highlighted exciting preclinical and clinical advances at the interface between RT and IT, setting the stage for extra progress toward extended benefits for patients with an increasing variety of tumor types. Here, we critically summarize the lines of investigation that have been discussed at the occasion of the 8th Annual ImmunoRad Conference.

Metastasis-directed therapies such as stereotactic body radiotherapy (SBRT) are increasingly used in patients with metastatic cancer with limited disease burden. Although effective for local control, emerging evidence suggests that SBRT may have unintended systemic effects that reshape the tumor-immune landscape. A recent study identifies amphiregulin (AREG), an EGFR ligand, as a key mediator of radiation-induced changes in metastatic behavior. In clinical cohorts and murine models, SBRT led to marked AREG upregulation. Rather than promoting tumor cell proliferation directly, AREG acted through the myeloid compartment, inducing monocyte differentiation into immunosuppressive macrophages and enabling immune escape. Elevated AREG-either at baseline or following SBRT-was associated with increased metastatic progression and inferior survival. Mechanistically, AREG signaling induced CD47 expression on tumor cells, further impairing macrophage-mediated clearance. Therapeutically, AREG blockade, especially combined with anti-CD47 antibodies, synergized with radiotherapy to suppress both local and distant diseases in preclinical models. These findings reveal both challenges and opportunities: whereas radiation effectively suppresses new metastatic seeding, it may reorganize the biological ecosystem in ways that unmask dormant disease. Understanding these dual effects offers therapeutic opportunities through combination approaches targeting radiation-induced pathways. AREG emerges as both a biomarker and therapeutic target. Integrating biomarker-informed strategies with metastasis-directed therapies may be essential for achieving durable disease control and optimizing outcomes in metastatic cancer.

Introduction: Many patients with muscle-invasive bladder cancer are poor candidates for radical cystectomy or trimodality therapy with maximal transurethral resection of bladder tumor (TURBT) and chemoradiotherapy with cisplatin or mitomycin C. Given the benefit of chemotherapy in bladder-preserving therapy, less-intense concurrent chemotherapy regimens are needed. This study reports on efficacy and toxicity for patients treated with trimodality therapy using single -agent concurrent capecitabine. Materials and Methods: Patients deemed ineligible for radical cystectomy or standard chemoradiotherapy by a multidisciplinary tumor board and patients who refused cystectomy were included. Following TURBT, patients received twice-daily capecitabine (goal dose 825 mg/m(2)) concurrent with radiotherapy to the bladder + /-; pelvis depending on nodal staging and patient risk factors. Toxicity was evaluated prospectively in weekly on-treatment visits and follow-up visits by the treating physicians. Descriptive statistics are provided. Overall, progression-free, cancer-specific, distant metastasis-free, and bladder recurrence-free survival were estimated using the Kaplan-Meier method. Results: Twenty-seven consecutive patients met cr iter ia for inclusion from 2013 to 2023. The median age was 79 with 9 patients staged cT3-4a and 7 staged cN1-3. The rate of complete response in the bladder and pelvis was 93%. Overall, progression-free, cancer-specific, distant metastasis-free, and bladder recurrence-free survival at 2 years were estimated as 81%, 65%, 91%, 75%, and 92%, respectively. There were 2 bladder recurrences, both noninvasive. There were 7 grade 3 acute hematologic or metabolic events but no other grade 3 + toxicities. Conclusion: Maximal TURBT followed by radiotherapy with concurrent capecitabine offers a high rate of bladder control and low rates of acute and late toxicity.

Supplementary figure 2. Gene expression pathways are enriched for PD-L1 production and leukocyte migration in lung of irradiated mice.

The majority of cancer patients receive radiotherapy during the course of treatment, delivered with curative intent for local tumor control or as part of a multimodality regimen aimed at eliminating distant metastasis. A major focus of research has been DNA damage; however, in the past two decades, emphasis has shifted to the important role the immune system plays in radiotherapy-induced anti-tumor effects. Radiotherapy reprograms the tumor microenvironment, triggering DNA and RNA sensing cascades that activate innate immunity and ultimately enhance adaptive immunity. In opposition, radiotherapy also induces suppression of anti-tumor immunity, including recruitment of regulatory T cells, myeloid-derived suppressor cells, and suppressive macrophages. The balance of pro- and anti-tumor immunity is regulated in part by radiotherapy-induced chemokines and cytokines. Microbiota can also influence radiotherapy outcomes and is under clinical investigation. Blockade of the PD-1/PD-L1 axis and CTLA-4 has been extensively investigated in combination with radiotherapy; we include a review of clinical trials involving inhibition of these immune checkpoints and radiotherapy.

Background Immunotherapy in combination with chemotherapy is first-line treatment for patients with extensive-stage small-cell lung cancer (ES-SCLC). Growing evidence suggests that radiation, specifically stereotactic body radiation therapy (SBRT), may enhance the immunogenic response as well as cytoreduce tumor burden. The primary objective of the study is to determine the progression free survival for patients with newly diagnosed ES-SCLC treated with combination multi-site SBRT and chemo-immunotherapy (carboplatin, etoposide, and durvalumab). Methods This is a multicenter, single arm, phase 2 study. Patients with treatment-naïve, ES-SCLC will be eligible for this study. Patients will receive durvalumab 1500mg IV q3w, carboplatin AUC 5-6 mg/mL q3w, and etoposide 80-100mg/m2 on days 1-3 q3w for four cycles, followed by durvalumab 1500mg IV q4w until disease progression or unacceptable toxicity. Ablative radiation will be delivered to 1-4 extracranial sites in 3 or 5 fractions, determined by location, during cycle 2. The primary endpoint is progression-free survival, measured from day 1 of chemoimmunotherapy. Secondary endpoints include grade 3-4 toxicity by CTCAE v5.0 within three months of RT, overall survival, response rate, time to second line systemic therapy, and time to new distant progression. Conclusions Now that immunotherapy is an established part of ES-SCLC management, it is important to further optimize its use and effect. This study will investigate the progression-free survival of combined SBRT and chemo-immunotherapy in patients with ES-SCLC. In addition, the data from this study may further inform the immunogenic role of SBRT with chemo-immunotherapy, as well as identify clinical, biological, or radiomic prognostic features.

Supplementary figure 3. Gating strategy and PD-L1 in subsets of patient PBMCs

Background and purpose: Stereotactic ablative body radiotherapy (SABR) is an effective treatment for localized renal cell carcinoma (RCC). However, the role of primary site SABR for locally recurrent or metastatic RCC is unclear. Here, we report outcomes of primary SABR across a diverse cohort of localized, recurrent, and metastatic RCC patients treated at our institution. Materials and methods: RCC patients treated with SABR to lesions of the kidney or nephrectomy bed at our institution with at least 6 months of follow-up were included for analysis. Local control, overall survival, and freedom from distant failure were estimated using the Kaplan-Meier method. Estimated glomerular filtration rate (eGFR) was assessed at baseline and following SABR. Results: Fifty-three patients received primary site SABR. Thirty-seven (70 %) patients had localized RCC, and 16 (30 %) had metastatic RCC. Seven (13 %) had locally recurrent RCC after prior surgery or ablation. The median tumor size was 4.5 cm (IQR 3.7-6.3). At a median follow-up of 23 months (IQR 12-35), 2-year local control was 100 %, and 3-year local control was 94.4 % (95 % CI 84.4 %-100 %). Among patients with initially localized disease, the 2-year freedom from distant failure was 94.6 % (95 % CI 87.6 %-100 %), and the 2-year overall survival was 66.5 % (95 % CI 51.9 %-85.2 %). Twelve (23 %) patients experienced acute grade 1-2 treatmentrelated toxicity (nausea, vomiting, or small bowel). There were no acute grade 3-4 toxicities. Two (3.8 %) patients developed late grade 3 gastrointestinal toxicity. The median baseline eGFR was 51 mL/min/1.73 m2 (IQR 38-77). At 1-year post-SABR, the median eGFR decline was 5 mL/min/1.73 m2 (IQR -3 to 9). One patient required dialysis following SABR. Conclusion: This analysis demonstrates excellent local control rates across patients with localized, recurrent, and metastatic RCC treated with SABR. Treatment was associated with minimal eGFR decline.

Supplementary Figure 6. CXCL10 induces PD-L1 expression