Cancer Immunotherapy Roundup: New Preclinical Studies Target Tumor Evasion
A series of recent studies from different institutions have reported new approaches to cancer immunotherapy, targeting various mechanisms by which tumors evade the immune system. The studies, conducted in preclinical models, address cancers including ovarian cancer, glioblastoma, pancreatic cancer, and metastatic lung and ovarian cancers.
Ovarian Cancer: Overcoming Immune Suppression via Ascites and FAK
Two studies reported findings related to the treatment of ovarian cancer in preclinical models.
Ascites Fluid and Ferroptosis Resistance
A study from Duke University School of Medicine, published in Nature Communications, investigated how ascites fluid in advanced ovarian cancer patients protects cancer cells.
According to the study, ascites—present in 90% of advanced ovarian cancer cases—was found to block ferroptosis, a form of cell death involving iron and fat reactions. The researchers reported that protection required as little as 2% ascites concentration and was specific to ferroptosis, not affecting other cell death types.
Removal of lipids from ascites eliminated the protective effect, indicating lipids are key. The study also found that the cholesterol-lowering drug bezafibrate restored sensitivity to ferroptosis in the presence of ascites but did not induce cell death on its own or slow tumor growth in mice. The research involved experiments on cancer cell lines and patient-derived tumor cells.
"Targeting the tumor environment with repurposed drugs could make cancer cells more vulnerable to existing treatments."
The authors concluded that targeting the tumor environment with repurposed drugs could make cancer cells more vulnerable to existing treatments.
FAK Inhibition and Immune Cell Recruitment
Researchers from Sanford Burnham Prebys and the University of California San Diego published findings in Cell Reports on February 25, 2026. The study demonstrated a treatment approach in mice that increased tumor-fighting cells near tumors and enhanced immunotherapy effectiveness.
The team identified cellular changes that improved immune system penetration of tumor immunosuppression. Previous research indicated that an overabundance of focal adhesion kinase (FAK) protein is present in over 75% of high-grade serous ovarian cancer cases and correlates with reduced patient survival.
Using an aggressive, chemotherapy-resistant ovarian mouse tumor model, the study compared the effects of a FAK-blocking drug in combination with chemotherapy and immunotherapy. The combination of FAK-blocking drug, chemotherapy, and immunotherapy yielded the most significant improvements in immune cell recruitment, tumor size reduction, and survival time.
Researchers observed that FAK inhibition altered chemical signals from macrophages, which began broadcasting the chemical signaling protein CXCL13. This protein facilitated macrophages in recruiting B and T cells to form tertiary lymphoid structures. The authors recommended further research to prepare for potential clinical trials.
Glioblastoma: Cytokine-Armored CAR-T Cells
Scientists at the UCLA Health Jonsson Comprehensive Cancer Center developed a new CAR-T cell therapy described in a study published in Cancer Research. The therapy reprograms CAR-T cells to release interleukin-12 (IL-12) and decoy-resistant IL-18 (DR-18), which activate the immune system.
The therapy targets IL-13Rα2, a protein on glioblastoma cells. In mouse models, the approach improved tumor control, including against tumors with mixed cell populations. The study reported that pairing the treatment with a second CAR-T strategy targeting VEGF reduced side effects while maintaining anti-tumor activity.
The combination of IL-12 and DR-18 was identified as particularly potent, leading to a significant influx of immune cells into the brain. Researchers reported that the therapy eliminated tumors lacking the target antigen IL-13Rα2.
The researchers are completing preclinical studies and seeking funding for a Phase 1 clinical trial in patients with recurrent high-grade gliomas.
Pancreatic Cancer: LNP-Delivered CAR T Therapy
Researchers led by Ellen Puré from the School of Veterinary Medicine utilized lipid nanoparticles (LNPs) to generate CAR T cells directly within the body in a preclinical model of pancreatic ductal adenocarcinoma (PDAC).
The CAR T cells were engineered to target fibroblast activation protein (FAP), which is expressed on cancer-associated fibroblasts (CAFs) that form a dense desmoplastic barrier around tumors. The study reported that a single dose of targeted LNPs in a preclinical PDAC model inhibited tumor growth as effectively as, or more effectively than, the conventional CAR T cell approach.
The method resulted in a significantly higher percentage (40-60%) of T cells expressing the CAR within the tumor compared to typically less than 10% with conventional methods. Researchers observed the reduction of the desmoplastic matrix.
This approach offers a potentially alternative method to conventional CAR T cell therapy, which requires ex vivo cell engineering and reinfusion.
Metastatic Cancer: Targeting Tumor Macrophages
Scientists at the Icahn School of Medicine at Mount Sinai developed an experimental immunotherapy strategy published in Cancer Cell that targets macrophages protecting cancer cells.
The strategy involves engineered CAR T cells, derived from a patient's own T cells, designed to recognize tumor macrophages. The cells were further modified to produce interleukin-12, a molecule that activates killer T cells.
In preclinical models of metastatic lung and ovarian cancers, the CAR T cell treatment significantly extended survival in mice, with many animals experiencing a complete cure.
Advanced spatial genomics analysis indicated that the therapy altered the tumor environment, removing immune-suppressing cells and attracting cancer-killing immune cells. Researchers emphasized that human studies are required to confirm the safety and effectiveness of this approach.