Finding a tumor's soft spot to power-up immunotherapy

by Greta Harrison, Keck School of Medicine of USC

edited by Sadie Harley, reviewed by Robert Egan

Sadie Harley

Scientific Editor

Meet our editorial team
Behind our editorial process

Robert Egan

Senior Editor

Meet our editorial team
Behind our editorial process Editors' notes

This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility:

fact-checked

peer-reviewed publication

trusted source

proofread

The GIST Add as preferred source

Researchers at the USC Viterbi School of Engineering and Keck School of Medicine of USC have engineered a genetic tool that addresses one of the most persistent obstacles in cancer immunotherapy: the physical softness of tumors. The work, detailed in the journal Nature Biomedical Engineering, reveals how the soft environment of a tumor enables cancer cells to become "stealthy" and resistant to treatment, providing a mechanism to tag those evasive cells for destruction.

The paper's lead author, Jenny Yunjia Qu, a postdoctoral researcher in the lab of Peter Yingxiao Wang, the Dwight C. and Hildagarde E. Baum Department Chair in the Alfred Mann Department of Biomedical Engineering, collaborated with the USC Viterbi and Keck School of Medicine teams to develop a technique that targets hard-to-reach "cancer stem-like cells." These cell types possess stem cell-like abilities, including self-renewal, which make them key drivers of tumor growth, drug resistance and cancer recurrence.

The soft barrier to immune attack

CAR T-cell therapy is a cancer treatment in which T cells—a type of white blood cell—are removed from a patient and given a unique chimeric antigen receptor (CAR). The CAR binds to cancer cell-associated antigens, directing T cells to destroy cancer cells. CAR T-cell therapy has revolutionized the treatment of blood cancers, but it struggles against solid tumors.

The Wang Lab team has demonstrated the critical role of a tumor's physical microenvironment in the success of CAR T cells, particularly when that microenvironment is soft.

"This is a relatively new finding in the field—that soft environments can cause cancer cells to be less killable by CAR-T cell therapy, and other approaches," said Wang. "Soft environment cancer cells typically have a greater tendency to become stem cell-like cells, which is also consistent with resistance to being killed by CAR-T therapy."

Qu said the problem is like trying to puncture something gelatinous, such as Jell-O or tofu—the soft, springy nature of the material makes it difficult to penetrate.

"CAR T cells kill tumors by grabbing individual cells, poking holes in their membrane and secreting cytotoxic molecules into the tumor cells. When the CAR T cell is going in, they can really see, grab and kill the stiffer cells, but they neglect the softer, Jell-O-like ones," Qu said.

"The cells are soft, therefore they cannot be grabbed easily, so the CAR T cells have less efficacy in killing them," Wang said. "Jenny essentially identified the mechanism in these soft, stem-like tumor cells and used this understanding and molecular insight to rewire them so that they can produce more recognizable markers on their surface. This makes the cells more recognizable to CAR T cells, and therefore they can be attacked with a higher probability of being killed."

Barcoding treatment-resistant soft cells with a 'black box'

To address this immune evasion, the research team first needed a way to identify and track these evasive soft cells. They engineered a genetic tool called the Mechano-Recorder, which acts like a "black box" inside the cell. The tool records the level of mechanical softness the cell experiences. The researchers discovered that softer cancer cells displayed significantly higher intracellular calcium signaling.

The Mechano-Recorder converts this transient calcium signal into a stable, long-lasting fluorescent signal, effectively barcoding these cells with their mechanical experience.

"The recording part is the most exciting part," said co-author Longwei Liu, assistant professor of ophthalmology and biomedical engineering at USC. "It's just like you're taking a picture of the cancer cells at certain points in time and recording the signal for diagnostic purposes or for developing a therapeutic purpose."

The team then used this recorder to show that soft environments specifically promote recorder-positive cells, which exhibit stem cell-like features, including markers associated with metastasis and hypoxia.

The researchers then leveraged the Mechano-Recorder's design for therapeutic action, genetically reprogramming the system to convert the signature of soft, resistant cells into a targetable beacon for immune cell attack.

"What we are trying to do is first recognize the difference between the softer and the stiffer cells. And then we rewire the softer cells to express another synthetic antigen," Qu said.

Qu and her colleagues replaced the fluorescent reporter in the recorder with CD19, a clinically validated antigen commonly used in CAR T-cell therapy for blood cancers. This process effectively broadcasts a 'kill me' signal to CAR T cells.

"When the softer cells express this signal, the CD19 CAR T cells that we engineered will come in and only see those cells with the 'kill me' signal, and then they'll attack," Qu said.

"Finding the soft spot in solid tumors is a major new direction in making immune-mediated therapy a reality," said W. Martin Kast, a co-author and the Walter A. Richter Cancer Chair and professor of immunology and immune therapeutics at the Keck School of Medicine.

Broad impact for solid tumors

Tested in breast cancer cell lines, patient-derived cells and mouse models, the rewiring strategy overcame the resistance of soft cancer stem-like cells. The results showed that these reprogrammed tumors, though softer, exhibited greater T-cell infiltration and enhanced killing efficacy.

Wang added that the Mechano-Recorder and cell-barcoding system had broad applications across cancers and many other diseases beyond breast cancer tumors.

"This same approach could be readily applied or extended to other types of solid tumors—essentially all of them," Wang said. "In this particular work, we convert a soft-induced stimulus into a 'kill me' signal. But we can do the same thing for many other cell signals as well. Any molecular signaling pathway we detect, we can convert into a 'kill me' signal or a 'help me' signal, depending on what we need and what kind of disease we are dealing with."

The team has already tested the approach in models of glioblastoma, pancreatic cancer and prostate cancer.

Wang said that the team's latest work establishes a foundational concept: Understanding the molecular consequences of a cancer cell's biophysical cues, like softness, allows researchers to "steal" the molecular information and then wire it to behave in a way that is more beneficial to treatment.

By transforming a tumor's softness-driven stealth into an obvious target, the work paves a new path for improving immunotherapy outcomes.

Publication details

Yunjia Qu et al, Identifying and reprogramming softness-driven cancer stem-like cells overcomes CAR-T cell resistance in solid tumours, Nature Biomedical Engineering (2026). DOI: 10.1038/s41551-026-01722-7

Journal information: Nature Biomedical Engineering

Key medical concepts

Antigens, CD19CAR T Cell Therapy

Clinical categories

OncologyAllergy and immunology Provided by Keck School of Medicine of USC Who's behind this story?

Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries. Full profile →

Robert Egan

Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →

Citation: Finding a tumor's soft spot to power-up immunotherapy (2026, August 12) retrieved 12 August 2026 from https://medicalxpress.com/news/2026-08-tumor-soft-power-immunotherapy.html This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.