A polymer that targets cysteines shrinks tumors in mice

An injectable polymer therapy that takes advantage of the excess of cysteines on tumor cells can stimulate an immune response to fight many different types of cancers in mice (ACS Cent. Sci. 2022, DOI: 10.1021/acscentsci.2c00704).

Cancer vaccines rev up the body’s immune system to fight tumors, but many vaccines in development are complex and expensive because they must be tailored to a person’s specific cancer. The new approach “is much more tumor agnostic,” says Anna Slezak, a PhD student in molecular engineering at the University of Chicago, who coauthored the work.

In normal cells, cysteines usually pair up and link together during protein synthesis, but cancer cells churn out misfolded proteins in which cysteines often can’t link up, says Jeffrey Hubbell, who is Slezak’s supervisor. These unpaired cysteines carry free thiols, which are stabilized by the reductive environment in cancer cells.

Hubbell came up with the idea to use the thiol groups to latch onto the surface proteins of tumor cells. Once captured, those proteins could be presented to the immune system, triggering an immune response against them. By using living tumor cells and debris from dead tumors this way, the team aimed to make an “in situ vaccine” that would mount an attack on a person’s specific cancer.

To do this, they created a polymer containing three active parts: a disulfide group that binds to free thiols, which grabs onto tumor cells and debris; an immune-activating drug that attracts cytokines and other immune cells to the tumor material; and a sugar called mannose, which attracts dendritic cells that help the immune system recognize the tumor as harmful.

Injecting this polymer directly into tumors caused the tumors to shrink in a mouse model of colon cancer and slowed tumor growth in models of skin and mammary cancer. When the researchers combined the injections with a regimen of already-approved cancer drugs called checkpoint inhibitors, the treatment worked even better.

Targeting cancer cells via excess thiols is a fresh approach, and the polymer the researchers created is straightforward and easy to make, says Steven J. Sucheck, a biological chemist at the University of Toledo who was not involved in the work. “I’m impressed with the results.”