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Four Studies Explore New Cancer Treatment Approaches Targeting Tumor Microenvironment

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Targeting the Tumor's Defenses: Four New Strategies for Hard-to-Treat Cancers

Recent research has produced four separate studies examining novel therapeutic strategies for difficult-to-treat cancers. The studies, published in Nature Communications, Cancer Cell, Cell Reports, and as a preclinical report from the University of Pennsylvania, focus on targeting the cellular environment surrounding tumors rather than the cancer cells themselves.

Study 1: Ascites Fluid and Ferroptosis in Ovarian Cancer

A study from Duke University School of Medicine, published in Nature Communications, investigated how ascites fluid affects ovarian cancer cell survival.

"Ascites fluid, present in approximately 90% of advanced ovarian cancer cases, was observed to protect cancer cells from ferroptosis."

Key Findings:

  • The protective effect required as little as 2% ascites concentration and was specific to ferroptosis—a form of cell death involving iron and fat reactions—not affecting other cell death types such as apoptosis or necrosis.
  • Removal of lipids from ascites eliminated the protective effect, indicating lipids play a role in this mechanism.
  • The cholesterol-lowering drug bezafibrate restored sensitivity to ferroptosis in the presence of ascites in laboratory experiments, but did not induce cell death on its own or slow tumor growth in mice.

The study involved experiments on cancer cell lines and patient-derived tumor cells. The authors suggested that targeting the tumor environment with repurposed drugs could potentially make cancer cells more vulnerable to existing treatments. The implications may extend to other cancers that spread within the abdominal cavity, such as colorectal and pancreatic cancers.

Support for the study came from the Ovarian Cancer Research Alliance, the Department of Defense, and the R.O.C. National Science and Technology Council. The senior author was Jen-Tsan Chi; the first author was Yasaman Setayeshpour.

Study 2: Immunotherapy Targeting Tumor Macrophages

Scientists at the Icahn School of Medicine at Mount Sinai developed an experimental immunotherapy strategy for metastatic cancer, published in Cancer Cell.

The Approach:

  • The strategy targets macrophages, immune cells that within tumors are reprogrammed to block immune attacks and help cancer survive.
  • The therapy uses engineered CAR T cells derived from a patient's own T cells. Unlike traditional CAR T cells designed to kill cancer cells, these were engineered to recognize tumor macrophages.
  • The CAR T cells were further modified to produce interleukin-12 (IL-12), a molecule that activates killer T cells.

Preclinical Results:

  • In preclinical models of metastatic lung and ovarian cancers, the CAR T cell treatment extended survival in mice, with some animals experiencing complete remission.
  • Advanced spatial genomics analysis indicated the therapy altered the tumor environment, removing immune-suppressing cells and attracting cancer-killing immune cells.

Researchers noted that human studies are required to confirm safety and effectiveness. The findings are considered a proof of concept, and the team is continuing to refine the therapy.

Study 3: FAK Protein Inhibition in Ovarian Cancer

Researchers from Sanford Burnham Prebys and the University of California San Diego published findings in Cell Reports on February 25, 2026.

Background:

  • Focal adhesion kinase (FAK) protein overabundance, caused by genetic mutations, is present in over 75% of high-grade serous ovarian cancer cases and has been correlated with reduced patient survival.
  • Preclinical studies combining FAK-blocking drugs with chemotherapy have shown promise, leading to an ongoing Phase II clinical trial.

Experimental Approach:

  • Scientists used an aggressive, chemotherapy-resistant ovarian mouse tumor model with mutations similar to high-grade serous ovarian cancer.
  • The study compared a FAK-blocking drug combined with chemotherapy and immunotherapy against each treatment alone and a no-treatment control group.
  • Researchers measured B and T cell levels, tumor size, and survival duration.

Results:

  • 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, specifically increasing the signaling protein CXCL13. This protein facilitated macrophages in recruiting B and T cells to form tertiary lymphoid structures, which act as anti-tumor bases.

David Schlaepfer, PhD, was the senior and corresponding author. Xiao Lei Chen, MS, was the first author. The study received support from the National Institutes of Health, National Cancer Institute, National Science Foundation, V Foundation, and Sigrid Juselius Foundation.

Study 4: LNP-Delivered CAR T Therapy for Pancreatic Cancer

Researchers led by Ellen Puré from the University of Pennsylvania School of Veterinary Medicine reported a preclinical method for treating pancreatic ductal adenocarcinoma (PDAC).

Background:

  • PDAC presents treatment challenges due to a dense desmoplastic matrix that shields tumors and suppresses immune responses.
  • This microenvironment has limited the effectiveness of chimeric antigen receptor (CAR) T cell therapy.

The Approach:

  • The team used lipid nanoparticles (LNPs) to generate CAR T cells directly within the body (in vivo) in a preclinical model.
  • The CAR T cells were engineered to target fibroblast activation protein (FAP), which is highly expressed on cancer-associated fibroblasts (CAFs) that contribute to the desmoplastic barrier.

Results:

  • A single dose of targeted LNPs (tLNPs) in a preclinical PDAC model inhibited tumor growth as effectively as, or more effectively than, conventional CAR T cell approaches.
  • The tLNP method resulted in a higher percentage of T cells expressing the CAR within the tumor (40-60%) compared to conventional methods (typically less than 10%), though for a shorter duration.
  • Researchers observed a "reduction" of the desmoplastic matrix.

Researchers proposed that this LNP-based CAR T cell approach could potentially be combined with other therapies and may be effective against metastatic cancer. They also suggested the strategy could have applications beyond cancer, including fibrosis, autoimmunity, arthritis, and wound scarring.

Ellen Puré is a professor and director of the Penn Vet Cancer Center. The work received support from Capstan Therapeutics and Alliance for Cancer Gene Therapy.