-Kaohsiung Medical University-

How can the powerful anticancer immune response of cytokines be concentrated within tumors while reducing systemic toxicity? Associate Professor Wen-Wei Lin of the School of Post-Baccalaureate Medicine at Kaohsiung Medical University (KMU) has received the 2026 Ta-You Wu Memorial Award for his research, “Engineering a Steric-Hindrance-Mediated Cytokine Masking Platform for Improved Therapeutic Index and Reduced Toxicity in Cancer Immunotherapy.” Focusing on IL-12, a cytokine with potent immune-activating properties, Lin and his research team developed the Protease-Unlock and Steric-Hindrance (PUSH) system. The system acts like a “safety lock” for IL-12, temporarily masking its activity while it circulates throughout the body and restoring its activity once it reaches the tumor, with the goal of improving the therapeutic index while reducing systemic toxicity.

Lin has long been engaged in cancer research and therapeutic development. He explained that conventional anticancer therapies have primarily focused on directly attacking cancer cells. In recent years, however, researchers have increasingly recognized that the tumor microenvironment also plays a critical role in determining treatment outcomes. When the tumor microenvironment becomes immunosuppressive, existing therapies may not achieve their full potential, allowing cancer cells to evade treatment. Improving the tumor microenvironment and restoring local immune activity have therefore become important strategies for enhancing cancer treatment.

Among cytokines, IL-12 has potent immune-activating and antitumor properties and can help initiate immune responses, but its therapeutic application also presents significant challenges. Lin explained that prolonged systemic activity of IL-12 can lead to excessive immune activation and systemic toxicity. In addition, its short half-life in the body limits its potential as a cancer therapeutic. Finding a way to preserve IL-12’s anticancer activity while reducing systemic toxicity therefore became a key challenge for the research team.

To address this challenge, the team developed the PUSH masking platform, which temporarily suppresses IL-12 activity through steric hindrance. Lin describes the design as a “safety lock.” While IL-12 circulates throughout the body, the masking structure sterically blocks the region responsible for receptor binding, temporarily preventing IL-12 from exerting its biological activity and thereby reducing systemic toxicity. Once the masked IL-12 reaches the tumor, specific proteases within the tumor microenvironment can cleave away the masking structure, effectively “unlocking” IL-12 and restoring its activity so that it can trigger an immune response locally within the tumor.

“We hope to make cytokines work where they are supposed to,” Lin said. A number of approaches are currently being explored internationally to reduce the systemic toxicity of cytokine therapies. Some strategies use affinity-based masking designs, in which a masking structure binds to the cytokine. However, when the cytokine needs to be reactivated, the affinity between the two components may make complete separation difficult, potentially reducing reactivation efficiency.

The PUSH platform instead uses steric hindrance without introducing additional affinity interactions between the masking structure and the cytokine. Once the protease removes the masking structure, the two components can separate more completely, potentially improving IL-12 reactivation efficiency and enhancing its anticancer effects.

Another potential application of the platform is its future combination with existing cancer immunotherapies. Lin noted that the effectiveness of some immune checkpoint inhibitors and antibody-based targeted therapies depends on sufficient immune activity within the tumor microenvironment. However, as cancer progresses or treatment continues, tumors may gradually develop an immunosuppressive microenvironment, allowing cancer cells to evade treatment and potentially spread further. In the future, locally reactivating IL-12 through the PUSH platform and combining it with existing therapies may offer a potential strategy for improving treatment responses and outcomes.

The technology is currently still at the preclinical research stage, and further development and validation will be required before clinical application. Lin estimates that another five to ten years of research and validation may be needed. Going forward, the team will continue investigating challenges associated with the tumor microenvironment, including excessive extracellular matrix expression, irregular tumor vasculature, and tumor heterogeneity. The team will also explore potential combinations with existing cancer therapies, with the aim of further improving overall treatment efficacy.

Reflecting on receiving the award, Lin said he felt not only happy but also “a sense of relief.” When he first proposed the research concept, he inevitably faced skepticism. After having research proposals rejected several times, he admitted, “Sometimes I even doubted myself.” He sees the award as an important encouragement for himself and his team after years of dedication to the research.

Lin expressed special appreciation to his university and doctoral advisor, Professor Tian-Lu Cheng, former Vice President of KMU, as well as the students and team members who have contributed to the research. He noted that Professor Cheng has long encouraged students to consider, from the very beginning of a research project, how their findings might eventually be translated into clinical applications and contribute to human health. This philosophy of “conducting research that makes a difference” has become an important principle guiding Lin’s research direction. He also expressed gratitude to KMU for supporting the team’s continued research through university-level and university-hospital research programs.

▲KMU Associate Professor Wen-Wei Lin receives the 2026 Ta-You Wu Memorial Award for his research, “Engineering a Steric-Hindrance-Mediated Cytokine Masking Platform for Improved Therapeutic Index and Reduced Toxicity in Cancer Immunotherapy.”

▲Lin’s research team performs protein purification for pro-cytokine drug development.

▲Lin’s research team conducts functional testing of pro-cytokine proteins.