Vanderwalde, A. | Search bioRxiv

bioRxiv2026

ATM functions as a rheostat of metabolic stress in small-cell lung cancer

ATM is best known as a guardian of genomic stability, yet its contributions to oncogenic signaling in aggressive malignancies like small-cell lung cancer (SCLC) remain poorly understood. Despite ATM being an established clinical vulnerability in SCLC, its influence on dysregulated tumorigenic circuits remains unclear. We demonstrate that inhibition of ATM disrupts the AKT-mTORC1-4EBP1 signaling axis, leading to attenuation of the master regulator of stress, ATF4. ATF4 and MYC appear to co-regulate one another in a feedback loop critical for redox homeostasis. ATM inhibition perturbs both the expression and function of MYC and ATF4, leading to increased intracellular reactive oxygen species, impaired glutathione recycling, and ferroptotic cell death, thereby exposing a crucial dependency of SCLC on stress-adaptive signaling. We uncover previously unrecognized metabolic vulnerability in SCLC, nominating ATM as a regulator of adaptive stress, expanding its role beyond canonical DNA damage repair (DDR) and highlighting therapeutically exploitable opportunities in aggressive tumors. Statement of SignificanceThe metabolic landscape of SCLC remains poorly characterized, particularly its interaction with dysregulated signaling networks, limiting the development of effective strategies to overcome therapeutic resistance. Our work reveals an expanded role for ATM beyond DNA repair, positioning it as a key regulator of metabolic rewiring and highlighting new therapeutic opportunities for SCLC.

cancer biology↗

bioRxiv2025

Perturbational single-cell profiling of patient tumors defines lineage- and context-specific programs of innate immune resistance

AbstractDespite promise in preclinical models, most immuno-oncology drug candidates fail in clinical trials. These failures reflect limitations in our ability to directly model the response of human tumor and immune cells to immunotherapies. To address this gap and test the effect of innate immune agonists, we developed PERCEPT, an approach that uses ex vivo perturbational single-cell RNA sequencing to compare the response of immunomodulatory treatments with unstimulated controls directly in patient samples. Using PERCEPT, we tested cytokines and innate immune agonists in melanoma and Merkel cell carcinoma (MCC) and identified the dsRNA mimetic, RIG-I agonist, Stem Loop RNA (SLR) 14 as a powerful inducer of anti-viral states and enhancer of T cell activation. We compared transcriptional responder and non-responder patient samples and identified midkine (MDK), a multifunctional cytokine, as a potent repressor of IFN signaling in both tumor and immune cells. MDK expression dampened MHC-I presentation in human tumor cells and reduced activation of antigen-presenting cells, disrupting tumor immunity at multiple levels. In contrast to prior studies, we identified MDK as specifically enriched in neuroendocrine cancers such as MCC and small cell lung cancer compared with melanoma, suggesting the importance of lineage- and context-specific targeting. Our results demonstrate the utility of high-dimensional controlled perturbation of patient samples to identify mechanisms of innate immune response and resistance and demonstrate an actionable path towards clinical development of MDK-inhibiting therapies including FDA-approved ALK inhibitors in neuroendocrine cancers.

cancer biology↗