Colorectal cancer (CRC) is a heterogeneous malignancy, with various alterations in molecular signalling pathways driving disease progression and resistance to therapy. Liquid biopsy, as a source of circulating tumour DNA (ctDNA), has been utilized to characterize tumour molecular heterogeneity, facilitating the identification of actionable targets for precision medicine-guided therapies and the detection of emerging genomic drivers of drug resistance in patients with metastatic CRC. In addition, liquid biopsy-based analysis of ctDNA has been validated as a tool for detecting minimal residual disease (MRD) following locoregional treatment in patients with localized colon or rectal cancer, offering improved prognostic stratification and supporting the tailoring of adjuvant systemic therapy. Methodological evolution from PCR analysis of a few known mutations in one gene or a small panel of genes to the assessment of hundreds of genes and pathogenic variants by next-generation sequencing has enabled comprehensive genomic profiling (CGP), thereby improving knowledge of cancer molecular complexity at the individual patient level. In this respect, liquid biopsy-based CGP is an easily repeatable and minimally invasive approach that can provide a dynamic portrait of CRC molecular heterogeneity to guide personalized and adaptive treatment based on biomarkers of response and resistance. In this Review, we discuss current and potential roles of liquid biopsy-based ctDNA analysis in the clinical management of metastatic CRC. We also discuss the evidence supporting implementation of liquid biopsy-based assessment of MRD to refine the management of locoregional CRC and potentially improve cure rates while reducing overtreatment of many patients.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with poor prognosis and limited benefit from immune checkpoint inhibitors (ICIs). Biomarker-driven patient stratification has been hindered by small biopsy samples, high tumor heterogeneity, and the limited predictive value of PD-L1 and tumor mutation burden. Mitochondrial antiviral-signaling protein (MAVS) has emerged as a potential immune activation marker, particularly in patients receiving DNA-damaging therapies. We report a proof-of-concept clinical study evaluating a surface plasmon resonance–plastic optical fiber (SPR‑POF) biosensor functionalized with anti-MAVS antibodies to detect the protein in serum from SCLC patients undergoing chemo-immunotherapy, with or without radiotherapy. The biosensor achieved a limit of detection of 0.13 nM in human diluted serum and demonstrated high selectivity against common serum proteins. In a cohort stratified as best responders (disease control >6 months) and non-responders (progressive disease as best response), MAVS levels measured in responders were on average tenfold higher than in non-responders, consistent with previous preclinical PBMC and western blot data. The SPR‑POF platform demonstrated portability, cost-effectiveness (estimated 5 USD/unit), and operational simplicity, highlighting its potential for point-of-care testing (POCT) applications. Although limited by small patient numbers, these findings support MAVS as a promising predictive biomarker in SCLC, warranting validation in larger prospective studies.

The journal retracts the article titled "AXL and MET Tyrosine Kinase Receptors Co-Expression as a Potential Therapeutic Target in Malignant Pleural Mesothelioma" [...].

LBA3503 Background: Leucovorin/5-FU in combination with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are common chemotherapies (chemo) used in 1L treatment (tx) of mCRC. In patients (pts) with BRAF V600E-mutant mCRC, BREAKWATER Phase 3 demonstrated clinically meaningful and statistically significantly improved ORR by blinded independent central review (BICR), PFS by BICR, and OS with 1L EC+mFOLFOX6 vs chemo ± bevacizumab (bev) (Kopetz Nat Med 2025; Elez N Engl J Med 2025). The BREAKWATER safety lead-in previously showed that EC+FOLFIRI was tolerable with promising antitumor activity. BREAKWATER Cohort 3 was therefore conducted to study EC+FOLFIRI. The primary endpoint (EP) of BREAKWATER Cohort 3 was met, demonstrating clinically meaningful and statistically significant improvement in confirmed ORR by BICR with EC+FOLFIRI (64.4%) vs FOLFIRI±bev (39.2%; control) (odds ratio 2.76 [95% CI 1.42, 5.35; one-sided P =0.001]) (Kopetz ASCO GI 2026). Reported here are PFS by BICR (key secondary EP), and updated OS and safety data from BREAKWATER Cohort 3. Methods: Eligible pts in Cohort 3 had untreated BRAF V600E-mutant mCRC, measurable disease (RECIST 1.1), and ECOG PS 0-1. Pts were randomized 1:1 to receive EC+FOLFIRI or control. The primary EP was ORR by BICR. The key secondary EP was PFS by BICR; other secondary EPs included OS and safety. Results: 147 pts were randomized to EC+FOLFIRI or control; the median follow-up for PFS was 18.0 and 14.4 mo, respectively, for OS it was 20.6 and 20.7 mo, respectively (data cutoff: Jan 6, 2026). Baseline demographics and disease characteristics were generally balanced between arms. EC+FOLFIRI demonstrated a clinically meaningful and statistically significant PFS improvement vs control, meeting the key secondary EP (Table). Prolonged OS was observed (Table). The median duration of study tx was 67.9 wk for EC+FOLFIRI and 32.1 wk for control. Discontinuation of chemo (± bev as appropriate for the respective tx arms) due to AEs was similar between arms (14% [EC+FOLFIRI] vs 10% [control]). Conclusions: BREAKWATER Cohort 3 demonstrated clinically meaningful and statistically significant ORR and PFS improvements and prolonged OS with EC+FOLFIRI vs control. The safety profile was consistent with that known for each agent with no new safety signals. EC+FOLFIRI expands practice-changing standard-of-care options to deliver pt-centered care for pts with BRAF V600E-mutant mCRC. Clinical trial information: NCT04607421 . EC+FOLFIRI (n=73) Control (n=74) mPFS (95% CI), mo 15.2 (13.6, NE) 8.3 (6.9, 9.8) PFS HR a (95% CI) 0.44 (0.27, 0.70)One-sided P =0.0002 mOS (95% CI), mo NE (21.0, NE) 20.3 (13.2, NE) OS HR a (95% CI) 0.56 (0.34, 0.94) 18-mo OS rate (95% CI), % 72.0 (60.0, 80.9) 54.5 (42.0, 65.4) n=71 n=68 Serious TEAEs, % 49 44 Maximum Grade 3/4 TEAEs, % 70 81 NE, not estimable; TEAE, tx-emergent adverse event. a Stratified by ECOG PS (0 vs 1) at randomization.

Pancreatic ductal adenocarcinoma is traditionally characterized as a glycolytic tumor. However, the extent and clinical relevance of its metabolic heterogeneity remain poorly understood. In this study, we investigated whether glycolytic activity follows a consistent expression pattern across pancreatic ductal adenocarcinoma patients and explored how metabolic diversity influences therapeutic responses. Using spatial transcriptomics of ex vivo primary human pancreatic ductal adenocarcinoma specimens, along with single-cell and bulk RNA sequencing, we mapped glycolytic heterogeneity within the tumor microenvironment. Patient-derived cell models representing distinct glycolytic phenotypes were employed to assess metabolic profiles and responses to glycolytic pathway inhibition. A multiomics approach—including metabolomics, proteomics, and lipidomics—was integrated through a robust bioinformatics pipeline to identify pathway-specific variations. Our findings revealed pronounced glycolytic heterogeneity across pancreatic ductal adenocarcinoma tumors, with distinct transcriptional profiles that maintained cellular identity and spatial architecture. These glycolytic patterns are associated with clinical outcomes, suggesting their potential as prognostic indicators. Functional studies confirmed differential sensitivity to metabolic inhibitors in organoids and demonstrated their safety across models, supporting the therapeutic relevance of glycolytic stratification. Overall, this study reveals clinically significant metabolic heterogeneity in pancreatic ductal adenocarcinoma and proposes a glycolysis-based framework for patient stratification, which could guide personalized metabolic therapies and advance precision oncology in pancreatic cancer.

This case report describes the clinical management of a 68-year-old man with concurrent invasive melanoma and metastatic castration-resistant prostate cancer (mCRPC). Initially diagnosed with BRAF V600E-mutated melanoma, he received Dabrafenib and Trametinib. Later, prostate cancer was diagnosed with bilateral pulmonary metastases. Despite initial treatment with Triptorelin, Docetaxel, and Abiraterone, disease progression occurred. A liquid biopsy revealed an extremely high Tumor Mutational Burden (TMB) and mutations including POLE, BRCA2, ATM, and TP53. Due to the high TMB, off-label Pembrolizumab was initiated. Radiological evaluations at 3 and 6 months showed a marked response, with disappearance of target lung metastases and durable remission maintained through February 2025. Only grade 1 asthenia was reported, without significant treatment interruptions. This case illustrates the value of precision medicine and the role of liquid biopsy in guiding immunotherapy decisions for complex oncological cases. It supports the relevance of molecular profiling in selecting effective treatments beyond standard indications.

Despite advances in precision medicine, therapeutic options for pancreatic adenocarcinomas are limited, alongside a significant increase in incidence and mortality in recent years. We present the case of an exceptional response to immunotherapy in a heavily pre-treated pancreatic adenocarcinoma. The patient is a 73-year-old man that was diagnosed in 2017 with locally advanced pancreatic adenocarcinoma. He underwent different lines of chemotherapy and after exhausting standard treatment options, he practiced the FoundationOne® CDx analysis (Foundation Medicine, Inc., Cambridge, MA, USA), that pointed out a High Tumor mutational burden that permitted our Oncology Center to request Pembrolizumab 200mg flat dose q 21 as an off-label therapy. The patient started the treatment in July 2021 and is still ongoing, having achieved a complete radiological response of hepatic metastases. Although immunotherapy is not part of the standard treatment paradigm for advanced pancreatic cancer, our case suggests that it may provide substantial and durable clinical benefit in a small molecularly selected subgroup of patients who have exhausted conventional therapeutic options, highlighting the critical role of comprehensive molecular profiling in identifying actionable treatment opportunities.

Introduction:Metastatic melanoma has historically had a poor prognosis; however, survival has improved with immunotherapies, such as PD-1 and CTLA-4 inhibitors, and molecular targeted therapies for BRAF-mutant tumors. The combination of nivolumab and ipilimumab is highly effective, though with increased rates of toxicity. In Italy, since January 2022, such therapeutic combination has been approved and reimbursed only for metastatic melanoma patients with brain metastases or with PD-L1 expression <1%. Methods:We conducted a real-world study in six academic centers in southern Italy and analyzed the efficacy and toxicity outcomes in 72 patients. Results:The response rate was 54% (39/72) and, after 13.6 months of median follow-up, a longer median progression-free survival [17.03 months (95% CI 4.8-18.6)] compared to the pivotal CheckMate-067 trial or to other real-world studies. Better survival correlated with objective responses (p<0.0001) and low disease burden (less than three metastatic sites) (p=0.0415). All patients achieving an objective response had tumors with high or intermediatetumor mutational burden. The rates of immune-related adverse events were similar to those reported in the literature, but there was a lower therapy discontinuation rate. This might be due to more appropriate managing of emerging immunotherapy toxicities.

e15553 Background: Antiangiogenic agents are widely used in mCRC. The ABACO trial recently showed that high angiogenesis genes expression in tumor samples, correlates with response to Cabozantinib. However, genomic predictors are poorly reproducible in clinical practice. The RADIANCE trial evaluates whether radiological biomarkers could predict antiangiogenics efficacy. Methods: We conducted a retrospective, observational study of mCRC patients (pts), progressed after ≥2 systemic regimens, treated with Cabozantinib (Cabo), Trifluridine–Tipiracil plus Bevacizumab (TT+B), Regorafenib (Rego), or Trifluridine–Tipiracil (TT) alone. Pts required ≥ 1 measurable lesion per RECIST 1.1 on baseline CT-scan. Radiological features assessed included intratumoral vascularization (ITV) (ΔHU portal–unenhanced > or ≤ 20), calcification (Calc) (Humax > or ≤ 150), and density (Dens) (HUbasal > or ≤ 50). Results: 63 pts with heavily pretreated mCRC were included. 19 pts received respectively Cabo and TT+B, 15 TT and 10 Rego. Liver and peritoneal metastases were the main target lesions studied across cohorts. ITV was significantly associated with improved outcomes in pts treated with antiangiogenics. In the Cabo cohort, pts with metastases showing higher ITV experienced a significantly longer median PFS (4.14 vs 2.03 months (mo); HR 0.30, p = 0.037) and a higher DCR (77.8% vs 25%). In the TT+B and Rego cohorts, a favorable trend in PFS (8.05 vs 3.63 mo and 5.11 vs ~1 mo respectively) was observed in the same subgroups. In TT+B treated pts, greater ITV was also associated with a significantly higher DCR (90.9% vs 25%, p = 0.006). Among all pts treated with antiangiogenics (n = 45), higher ITV correlated with statistically significant longer PFS (5.22 vs 2.33 mo; HR 0.45, p = 0.012) and higher DCR (75% vs 19%, p = 0.00028). No association was observed in pts treated with chemotherapy (Cht) alone. Absence of baseline Calc (HUmax ≤150) showed a consistent, though non-significant, trend toward improved PFS and DCR in antiangiogenic-treated pts, in particular in TT+B and Cabo cohorts, while no benefit was observed with Cht alone. No association, instead, between baseline metastases Dens and clinical outcomes was observed. An integrated model combining ITV and Calc stratified pts into 4 prognostic groups, with progressively decreasing PFS and DCR. Pts with high ITV and non-calcified metastases achieved the best outcomes (mPFS 7.52 mo; DCR 80%). A radiological predictive score based on ITV and Calc was, therefore, developed (high/low ITV: 2/0, Calc yes/no: 0/1). A composite score ≥2 identified patients with a higher likelihood of benefit from antiangiogenics. Conclusions: Our work points out that ITV and absence of Calc, at baseline CT-scan, may be associated with benefit from antiangiogenics. Findings are preliminary and need validation in larger prospective cohorts.

Background: Airway stents are a palliative treatment for malignant central airway obstruction (MCAO). Reopening airways improves symptoms so that patients can undergo additional treatments such as chemo/radiotherapy. Airway stents may be withdrawn in case of tumoral response to treatment. However, stent fracture and airway injury are some complications reported after stent removal. Herein, we evaluated the feasibility of stent removal after MCAO. Methods: This was a retrospective study including consecutive patients treated with airway self-expandable metallic stent insertion and subsequent chemo/radiotherapy for MCAO between June 2018 and June 2024 at our institution. Patients were divided in 2 groups: stent removal group and control group. The decision of removing the airway stent was based on response to therapy. Results: Of the 72 included patients, 14 underwent stent removal. The median interval between stent placement and removal was 6 months and no intra- or periprocedural complications were observed. In 3 cases, the stent was removed after dislocation consequent to the tumoral response. Stent removal was associated with significant reduction of bronchoaspiration, infection, and granulation tissue formation, in addition to an increased overall survival (P = .029) and a lower 90-day mortality (P = .05) due to the better response to the therapy. Conclusions: Airway stent removal after chemo/radiotherapy is safe and feasible, and not associated with severe complications in expert hands. In case of significant reduction of the tumor, patients should be considered for stent removal to reduce complications related to the stent presence.

Introduction: Metastatic colorectal cancer (mCRC) constitutes approximately 10% of all cancers globally and ranks as the second leading cause of cancer-related deaths. Management of refractory mCRC remains challenging due to pharmacological resistance and limited effective therapeutic options. Methods: This publication presents insights from a Delphi panel of Italian clinicians regarding mCRC therapeutic approaches, unmet medical needs, and fruquintinib’s potential clinical utility within existing treatment algorithms. The project, guided by four leading Italian oncology experts, involved two survey rounds among 14 oncologists, achieving consensus on 15 statements with a 100% response rate. Results: The expert panel identified critical epidemiological patterns in mCRC, with 20-25% of patients requiring further treatment after the failure of third-line therapy. The panel emphasized the clinical significance of fruquintinib’s efficacy and tolerability profile demonstrated in the FRESCO-2 trial. The experts unanimously endorsed fruquintinib as a new standard of care for adult mCRC patients who have progressed through available standard therapies. Conclusions: This recommendation is based on fruquintinib’s observed survival benefit and manageable toxicity profile, which facilitate improved treatment management and potentially enhance patient quality of life. The structured consensus approach validates these recommendations, providing practical guidance for optimizing outcomes as therapeutic options for mCRC continue to expand in complexity.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by a dense desmoplastic tumor microenvironment (TME) that limits drug penetration and promotes immune evasion. Effective treatment, therefore, requires simultaneous modulation of multiple signaling pathways. Here, we describe a directed polypharmacological strategy to identify dual modulators of c−MET and Smoothened (SMO), aiming to disrupt the protective stroma through SMO inhibition while directly suppressing tumor cell survival via c−MET targeting. An AI−guided virtual screening workflow combining the machine−learning platform PyRMD, trained on known c−MET and SMO ligands, with structure−based molecular docking was applied to a library of over 9 million compounds. This approach led to the identification of compound 21, an aminopyrimidine−benzamide−phenoxyquinoline derivative, as a dual c−MET/SMO inhibitor. Biochemical and cellular studies demonstrated that compound 21 selectively binds the SMO orthosteric site (pKi = 5.60), inhibits agonist−induced GLI (Glioma−associated oncogene) signaling (pIC50 = 5.50), and potently suppresses c−MET kinase activity (pIC50 = 6.94). Western blot analyses further revealed that compound 21 promotes ubiquitin−proteasome−mediated degradation of c−MET, eliminating receptor availability and limiting compensatory resistance signaling. In 3D heterotypic models comprising MIAPaCa2 pancreatic cancer cells and CAF154−hTERT fibroblasts, dual inhibition of SMO−mediated stromal support and c−MET−driven tumor progression resulted in greater cytotoxicity than the combination of the selective inhibitors Sonidegib and PHA−665752. Overall, compound 21 overcomes stromal−mediated resistance, enhances tumor cell death, and validates dual SMO/c−MET targeting as a promising single−agent therapeutic strategy for PDAC.

Cutaneous melanoma (CM) is an aggressive cancer since early stages. Stage IIB/C CM present significant recurrence risk. Recently, adjuvant immunotherapy demonstrated to increase recurrence-free survival (RFS) in this setting. Assess safety and efficacy of adjuvant immunotherapy for stage IIB/C CM in a real-world setting. Stage IIB/C CM patients treated with adjuvant immunotherapy in eight centers from the “Gruppo Oncologico Italia Meridionale” (GOIM) were retrospectively investigated. Data were collected over a median follow-up of 16 months. Ninety-six patients with a median age of 59 years were included. Most participants were male (64.6

13 Background: Leucovorin/5-FU in combination with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are common chemotherapies used in 1L mCRC. In patients (pts) with BRAF V600E-mutant mCRC, the Phase 3 portion of BREAKWATER (NCT04607421) demonstrated clinically meaningful and statistically significantly improved ORR by blinded independent central review (BICR), PFS by BICR, and OS with 1L EC + mFOLFOX6 vs chemotherapy ± bevacizumab (bev) (Kopetz Nat Med 2025; Elez N Engl J Med 2025). The safety lead-in portion of BREAKWATER previously showed that EC+FOLFIRI was tolerable with promising antitumor activity. The primary analysis results for EC+FOLFIRI vs FOLFIRI ± bev (control) from BREAKWATER Cohort 3 are reported here. Methods: Eligible pts in Cohort 3 had untreated BRAF V600E-mutant mCRC, measurable disease (RECIST 1.1), and ECOG PS 0-1. Pts were randomized 1:1 to receive EC+FOLFIRI or control. The primary endpoint (EP) is ORR by BICR; key secondary EP is PFS by BICR; and other secondary EPs include OS, DOR, time to response (TTR), and safety. Results: In Cohort 3, 147 pts were randomized (EC+FOLFIRI, n=73; control, n=74). Baseline demographics and disease characteristics were similar between arms (median age: 62 yrs; male: 46%; ECOG PS 0: 60%). At data cutoff (Mar 1, 2025), EC+FOLFIRI demonstrated a clinically meaningful and statistically significant improvement in confirmed ORR by BICR vs control (Table), meeting the primary EP. Responses observed with EC+FOLFIRI were rapid and durable. OS data were immature (median follow-up: 10.5 mo [EC+FOLFIRI] and 10.3 mo [control]) but suggested a potential survival benefit with EC+FOLFIRI vs control. Serious treatment-emergent adverse events (EC+FOLFIRI: n=71; control: n=68) occurred in 39.4% vs 36.8% of pts, respectively. The safety profile was consistent with that known for each agent. The addition of EC to FOLFIRI did not lead to substantial increases in FOLFIRI discontinuation (FOLFIRI [or bev] discontinuation: 9.9% vs 8.8%, respectively). Conclusions: BREAKWATER Cohort 3 demonstrated a clinically meaningful and statistically significant improved response rate that was rapid and durable with EC+FOLFIRI vs control in 1L BRAF V600E-mutant mCRC, with manageable toxicities and no new safety signals. These data support EC+FOLFIRI as a potential new standard of care in BRAF V600E-mutant mCRC. Clinical trial information: NCT04607421 . EC+FOLFIRI n=73 Controln=74 ORR, a % 64.4 39.2 Odds ratio (95% CI) P -value b 2.76 (1.42-5.35)0.001 Estimated medianresponse duration a,c (95% CI), mo NE (NE-NE) NE (7.0-NE) Pts with a response duration of ≥6 mo, a,c % 57.4 34.5 Median TTR a,c (range), weeks 6.9 (5.4-36.1) 7.1 (5.9-25.3) Median OS (95% CI), mo NE (NE-NE) NE (12.1-NE) OS hazard ratio (95% CI) 0.49 (0.24-1.03) a By BICR. b One-sided α=0.025. c In responders: n=47 and n=29, respectively. NE, not estimable.

Cancer care for vulnerable populations such as migrants remains poorly investigated. The Campania Oncology Network (Rete Oncologica Campana, ROC) was established in Campania, a region of southern Italy, to ensure equitable access to cancer care. This study aimed to assess the proportion and distribution of cancers among migrants within the ROC. Data were extracted from the ROC digital platform for all cancer cases diagnosed between 2022 and 2025. Adjusted proportionate morbidity ratios (PMRs) were calculated to compare the most common cancer types between migrants and non-migrants. Among 78,119 adult cancer patients, 2,583 (3.3

Detection of the BRAF V600E mutation has important genetic, prognostic, and therapeutic implications for patients with metastatic colorectal cancer (mCRC), identifying a subgroup of patients who derive modest benefit from standard treatments and have extremely poor prognosis. The evolution of molecular profiling and the implementation of next generation sequencing in the evaluation of a patient with BRAF-mutated mCRC has currently led to the discovery of actionable alterations. Targeting multiple pathways of resistance in BRAF-mutated mCRC may be the most efficacious route. Then, over a short period of time, the treatment landscape BRAF-mutated mCRC patients has shifted dramatically. Finally, novel treatment strategies are available. This review will discuss on currently approved treatments for BRAF V600E mutated mCRC and will try and portray the changing landscape in this setting in the era of targeted molecular therapy.

Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by significant replication stress and DNA damage. Recently an "inflamed" subset of SCLC has been identified, showing high expression of genes associated with Stimulator of Interferon Genes (STING)-induced T-cell attracting chemokines, such as CCL5 and CXCL10. The addition of DNA damage repair inhibitors (DDRis) to immunotherapy has been shown to enhance immune responses through STING-dependent activation pathways.This study focuses on the role of DNA-PK inhibition (DNA-PKi), a key regulator of DDR, in the activation of multiple cytosolic DNA/RNA sensors (STING, cGAS, MAVS, IFI16) to elucidate the molecular mechanisms linking DNA damage to immune responses.Treatment-naïve SCLC patients (n=10) and patients undergoing chemotherapy treatment (n=10) were enrolled. Blood samples were collected at baseline and after chemo-immunotherapy to analyze the expression of cGAS, STING, MAVS, and IFI16. Comprehensive transcriptomic analysis, real-time PCR and protein analysis were performed. STING, MAVS and cGAS knockdown and subcellular localisation analysis were also reported.SCLC tumor tissues (n=81) with higher STING-related chemokines (CCL5/CXCL10) exhibited increased expression of genes involved in MAVS pathway (IFITH1, DDX60), suggesting a simultaneous activation of STING and MAVS. DNA-PKi enhanced STING and MAVS more effectively than other DDRis in SCLC patients-derived PBMCs post-cisplatin compared to naïve patients, indicating its unique role in promoting immune responses. No significant changes in cGAS expression were observed in immune cells from SCLC patients, suggesting that the upregulation of STING mediated by DNA-PK inhibition is independent of cGAS, as knockdown of cGAS did not influence the upregulation of STING and p-IRF3 following DNA-PKi treatment. DNA-PKi treatment resulted in novel mitochondrial co-localization and physical interaction between STING and MAVS in PBMCs, leading to improved functional activation via nuclear translocation of p-IRF3.In conclusion, the study posits that DNA-PK inhibition facilitates a non-canonical interaction between STING and MAVS, thereby enhancing the innate immune response against SCLC. Caterina De Rosa, Luisa Amato, Concetta Tuccillo, Francesca Iommelli, Viviana De Rosa, Virginia Tirino, Federica Papaccio, Kavya Ramkumar, Qi Wang, Jing Wang, Alberto Servetto, Floriana Morgillo, Lauren Averett Byers, Fortunato Ciardiello, Carminia Maria Della Corte. STING-MAVS interaction as novel immune mechanism of DNA-PK-inhibitor in SCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6158.