Senescence, the process where cells permanently stop dividing, has long puzzled cancer researchers: it can suppress tumors by halting uncontrolled growth, yet in some contexts it fuels cancer progression by altering the surrounding environment. This paradox is especially relevant in lung adenocarcinoma (LUAD), one of the most common and deadly forms of lung cancer. A recent Cell Stem Cell study by BARI member Tien Peng and his lab, resolves part of this puzzle by focusing on a specific subset of senescent cells within the tumor stroma (the supportive tissue around cancer cells). The study reveals that cancer-associated fibroblasts expressing p16Ink4a (a classic senescence marker) actively promote tumor aggressiveness by reprogramming cancer cell metabolism and identity. By developing ways to selectively eliminate these harmful fibroblasts, this study opens a promising avenue for treating advanced lung cancer through targeted clearance of senescent stromal cells.
Mapping senescence in the tumor microenvironment
To unravel how senescence influences cancer, the team employed spatial mapping techniques to locate and characterize senescent cells directly within intact tumor tissues. They focused on p16Ink4a+ cancer-associated fibroblasts (CAFs), which display multiple hallmarks of senescence, including persistent DNA damage signals and a pro-inflammatory secretome. In aggressive LUAD models driven by Kras and p53 mutations (common in human patients), these fibroblasts were enriched in the tumor stroma and showed a distinct metabolic profile.
Rather than simply halting proliferation, these senescent CAFs supported tumor growth by enhancing fatty acid uptake and utilization in nearby cancer cells. This metabolic rewiring provided the energy and building blocks needed for rapid tumor expansion. Moreover, the altered metabolism drove changes in tumor cell identity, pushing cells toward a dedifferentiated, highly plastic state (one in which cancer cells can shift phenotypes, evade therapies, and fuel progression and metastasis). Analysis of both mouse models and human LUAD samples confirmed these patterns, highlighting a conserved role for p16Ink4a+ CAFs in promoting aggressive disease
A senolytic screening platform identifies a key drug candidate
Recognizing that these senescent fibroblasts represent a vulnerability in the tumor ecosystem, the Peng team created an ex vivo senolytic screening platform. Senolytics are compounds designed to selectively kill senescent cells while sparing healthy ones. By culturing tumor-derived cells and testing a panel of candidates, they identified XL888, an inhibitor of HSP90, as particularly effective at clearing p16Ink4a+ CAFs.
HSP90 acts as a chaperone protein, stabilizing many client proteins essential for cell survival under stress, including in senescent states. Inhibiting it disrupted the survival mechanisms of these fibroblasts without broadly affecting non-senescent cells. Validation experiments showed that XL888 treatment eliminated the senescent CAFs from tumor cultures, thereby interrupting the metabolic support they provided to cancer cells. This approach was more precise than non-selective strategies, targeting the specific stromal component that drives malignancy.
Reducing tumor burden in advanced disease models
The therapeutic potential of XL888 was tested in vivo using mouse models of established, advanced LUAD. After tumors had progressed to a late stage, mimicking the clinical scenario where patients often present with metastatic disease, XL888 was administered systemically. The treatment significantly reduced overall tumor burden, as measured by tumor volume and weight. Histological examination revealed a marked depletion of p16Ink4a+ fibroblasts in the stroma, along with decreased fatty acid metabolism signatures in remaining cancer cells.
Importantly, the loss of stromal support coincided with a reduction in plastic, dedifferentiated tumor cells, those most resistant to therapy and prone to recurrence. No major toxicity was observed in healthy tissues, suggesting a favorable therapeutic window. These results demonstrate that eliminating senolytic-sensitive stromal fibroblasts, can starve aggressive cancer cells of essential metabolic resources, limiting their ability to maintain a malignant, adaptable state.
Why this matters for cancer treatment
This study advances our understanding of the tumor microenvironment by showing how senescence in non-cancer cells can paradoxically accelerate malignancy through metabolic crosstalk. In the broader field of oncology, it highlights stromal targeting as a complementary strategy to direct cancer cell therapies. Lung adenocarcinoma remains challenging due to its genetic heterogeneity and rapid adaptation; by disrupting the supportive niche provided by p16Ink4a+ CAFs, senolytics like XL888 could enhance existing treatments, such as targeted inhibitors for Kras-mutant tumors or immunotherapies.
For patients with advanced lung cancer, where options are limited and outcomes are poor, this approach offers hope for reducing disease progression without the broad toxicity of traditional chemotherapy. The identification of HSP90 inhibition as a senolytic mechanism builds on existing drugs in clinical development, potentially accelerating translation to human trials. While challenges remain, such as optimizing dosing, confirming long-term effects, and ensuring specificity across tumor types, the work underscores a shift toward precision targeting of the aging-relevant process of senescence in cancer.
What’s next for the Peng lab?
The Peng lab is studying how senescent fibroblasts alter immune cells with aging, particularly T cells that respond to immunotherapy in various cancers that preferentially afflict the elderly. This work could help unravel how aging tissues promote T cell dysfunction, and help to identify environmental factors in the aging tissue that alter a T cell’s ability to respond to immune-checkpoint blockade.