Targeting Key Protein Interactions Offers New Hope for Cancer Immunotherapy

Recent research from the University of Michigan has shed light on the crucial role of the interplay between two proteins, STAT3 and STAT5, in influencing tumor immunity and resistance to cancer immunotherapy. Immunotherapy, particularly immune checkpoint inhibitors, has revolutionized cancer treatment by enabling the immune system to target and destroy tumor cells. However, a significant challenge remains: many patients either do not respond effectively or develop resistance over time.

The study, published in Nature, reveals that the balance between STAT3 and STAT5 within dendritic cells—key immune cells responsible for activating T cells—determines the immune response against cancer. Higher STAT5 activity promotes dendritic cell maturation and enhances T cell activation, making tumors more susceptible to immune attack. Conversely, elevated STAT3 activity inhibits dendritic cell function, contributing to immune evasion by tumors.

By analyzing RNA sequencing data from cancer patients, researchers observed that those responsive to checkpoint inhibitors exhibited increased STAT5 signaling and decreased STAT3 activity. Using mouse models, the team confirmed that STAT3 counteracts the beneficial effects of STAT5, impairing the immune response.

Targeting STAT3 presents a promising therapeutic approach, but historically, it has been considered 'undruggable.' To overcome this, the researchers employed the body's natural protein degradation system, using molecules called SD-36 and SD-2301 to specifically target and degrade STAT3 in dendritic cells. This degradation boosted immune activity, increased STAT5 signaling, and proved effective against large, resistant tumors across various cancer types.

This innovative strategy paves the way for new treatments that could enhance the effectiveness of existing immunotherapies by rebalancing key immune-regulatory proteins. The next step involves clinical trials to evaluate the safety and efficacy of these STAT3 degraders, with the hope of benefiting a broad spectrum of cancer patients.

Source: https://medicalxpress.com/news/2025-05-interplay-key-proteins-cancer-treatment.html