One of the best ways to defeat cancer is by rousing the immune system to attack it.
Experts have thought that immune cells had to be inside of tumors for one type of immunotherapy, known as checkpoint inhibitors, to work. But new research from UCSF shows otherwise - creating the possibility that a wider range of tumors could be treated with immune-stimulating drugs.
The study reexamined immunotherapy clinical trial data on bladder and skin cancer and found that "cold" tumors, ones that haven't yet been infiltrated by immune cells, are just as vulnerable to checkpoint inhibitors as "hot" tumors, which have.
In mice, these cold tumors were defeated with a combination of radiation, immunotherapy and drugs that block a signal, TGF-Beta. Tumors use this signal to evade the immune system.
The findings were published on March 6 in the Journal for ImmunoTherapy of Cancer .
"In 2025, we have great options for treating many cancers, but it can be hard to determine which treatments will be most effective for a given patient," said Mary Helen Barcellos-Hoff , PhD, professor of radiation oncology at UCSF and senior author of the paper. "Our findings green light many more patients for immunotherapy, offering a faster path to remission and relief."
Tumors Under a Microscope
Two tumor samples colored to reveal the presence of lymphocyte immune cells.
Top: A "cold" tumor, which lacks lymphocytes (red), would normally be ineligible for immunotherapy with checkpoint inhibitors. But new UCSF research shows how cold tumors can be primed for treatment with checkpoint inhibitors.
Bottom: A "hot" tumor, which has been infiltrated by lymphocytes (red), and is already considered vulnerable to checkpoint inhibitor therapy.
Images by Barcellos-Hoff Lab
A surprising finding in clinical trial data
Normally, TGF-Beta soothes the immune system, and some cancers use it to evade attack. It also triggers a signaling cascade within cells to repair their DNA. Barcellos-Hoff wondered if certain tumors would be more vulnerable to immunotherapy if the TGF-Beta DNA repair system were undermined.
"Cancers with defects in DNA repair end up with more mutations and are susceptible to immunotherapy," Barcellos-Hoff said. "Since TGF-Beta promotes DNA repair, we wondered if low TGF-Beta signaling could point us to tumors with more mutations, which would be good candidates for immunotherapy."
Her team pored through past clinical trial data on immunotherapy drugs and bladder and skin cancer. They gave each tumor a score, called "beta-alt," that represented the degree of TGF-Beta signaling in the tumor along with the degree of DNA repair. Then they looked at whether immunotherapy had successfully treated each tumor.
As expected, in the clinical trials, tumors with high beta-alt (meaning, low TGF-Beta signaling and poor DNA repair) shrank in response to immunotherapy. Digging deeper into the data, though, the researchers made a surprising discovery.
"We expected the high beta-alt tumors to be inflamed, to be full of lymphocytes, but what we got was the exact opposite," Barcellos-Hoff said. "We found that high beta-alt is highly correlated with cold tumors that lack lymphocytes - tumors that are often ineligible for immunotherapy."
Heating up cold tumors for immune destruction
The biggest risk in cancer treatment is putting a patient on the wrong regimen ..."
The discovery seemed to contradict the idea that immunotherapy works best when there are lymphocytes inside of tumors. But further tests instead revealed a quirk in immune signaling that might be leveraged for the benefit of patients.
The cold tumors, which had diminished TGF-Beta signaling, were still, paradoxically, producing TGF-Beta - and warding off lymphocytes.
This created a new opening for cancer therapy, the researchers thought. If cold tumors were treated with a TGF-Beta blocker, it would open the door for immunotherapy to drive tumor-killing lymphocytes to the cold tumor and defeat it.
The team found that in mice, cold tumors could be treated with a TGF-beta blocker, radiation and immunotherapy.
Barcellos-Hoff hopes that beta-alt - which is based on data that oncologists already collect during cancer diagnosis and treatment - gives providers the confidence they need to prescribe immunotherapy to the patients who will benefit from it.
"Checkpoint inhibitors have been game changing for all sorts of cancers, and it's clear that even cold tumors benefit from them," Barcellos Hoff said. "The biggest risk in cancer treatment is putting a patient on the wrong regimen, and beta-alt takes much of the guesswork out of matching patient to treatment."
Authors: Other authors are Jade Moore, PhD, Jim Gkantalis, Ines Guix, PhD, William Chou, Kobe Yuen, PhD, Ann A. Lazar, PhD, Mathew Spitzer, PhD, and Alexis J. Combes, PhD.
Funding: This work was funded by the National Institutes of Health (NIH grants R01CA190980, R01CA239235, R01CA190980S1, T32CA108462, S10 OD018040, P30CA082103) and Genentech (imCORE network projects UCS-3, UCS-7, UCS-12).
