A pioneering research collaboration between Professor Won Jong Kim’s team from the Department of Chemistry and the POSTECH-Catholic Biomedical Engineering Institute at Pohang University of Science and Technology (POSTECH), alongside Dr. Junseok Lee’s group at UCLA, has introduced a transformative approach in cancer immunotherapy. Their innovative strategy, published in ACS Nano, harnesses a method that effectively bypasses the traditional dependency on tumor antigens by engineering tumor cells to present “fake targets” to immune cells. This breakthrough overcomes a significant barrier in current antibody therapy, offering a versatile and universal platform with substantial therapeutic potential.
Cancer immunotherapy has historically relied on identifying and targeting specific antigens expressed on tumor surfaces. However, most tumors present a heterogeneous or even absent antigen profile, severely limiting the effectiveness of these treatments. Tumors that do not express the targeted antigen—termed “antigen-negative tumors”—pose an insurmountable challenge, allowing malignant cells to evade immune surveillance and proliferate unchecked. This phenotypic plasticity renders conventional antibody therapies less effective, necessitating new strategies to engage the immune system irrespective of tumor antigen status.
Addressing these challenges, the research team devised a technology named “Universal Antibody” (Univody), which fundamentally transforms tumor cells by inducing the surface expression of antibody Fc fragments. This genetic modification turns tumor cells into artificial immune targets, independent of their intrinsic antigenic repertoire. The core of this technology rests on the stable presentation of Fc segments, a crucial portion of antibodies responsible for recruiting immune effector cells such as natural killer (NK) cells. By marking tumor cells with Fc fragments, the immune system can recognize and eliminate cancerous cells without needing tumor-specific antigen identification.
A key breakthrough enabling this novel approach is the development of a highly selective gene delivery vehicle termed Lipopolyplex modified with Phenylboronic Acid (LPP-PBA). This innovative delivery system exploits the elevated presence of sialic acid residues frequently overexpressed on cancer cell surfaces. The addition of PBA moieties to lipopolyplexes allows for targeted binding and selective penetration into tumor cells, ensuring that the genetic material encoding the Fc fragments is delivered precisely where it is needed. This tumor-selective delivery significantly minimizes off-target effects and enhances therapeutic efficiency.
Once the Fc fragments are displayed on the tumor surface, immune effector cells such as NK cells promptly identify and engage these modified cells. NK cells, pivotal players in innate immunity, bind to the Fc region through their Fc receptors and initiate cytotoxic activities. This interaction leads to direct tumor cell lysis and stimulates a cascade of immune activations that amplify antitumor responses. Experimental models in aggressive cancer types, including triple-negative breast cancer and melanoma, demonstrated that this approach substantially hindered tumor growth and improved survival outcomes.
This engineered modification of tumor cells represents a radical departure from conventional antibody therapies that require predefined antigen targets. By circumventing the need for tumor-specific antigens, the Univody platform offers unprecedented versatility. It provides an adaptable immune targeting mechanism potentially applicable across a broad spectrum of cancers, including those traditionally resistant to immunotherapies. This versatility marks a major leap forward in the design of universal cancer treatments that can overcome tumor heterogeneity complexities.
Professor Kim elucidated the significance of this technology, emphasizing its antigen-independent mode of action and implication for broad oncological applications. He highlighted that, unlike current antibody therapies constrained by tumor antigen expression variability, Univody’s universal design could revolutionize treatment paradigms. Complementing this, Dr. Junseok Lee underscored the innovative translational promise of directly tagging tumor cells with antibody fragments, which strategically bypasses critical limitations in existing immunotherapeutic approaches.
The clinical implications of this research extend beyond efficacy. The use of genetic constructs to induce antibody fragment expression on tumor surfaces introduces a novel class of antitumor agents. This approach leverages the natural cytotoxic functions of immune cells while providing specificity through the artificial tagging of tumors. Additionally, the biocompatibility and tumor-selective delivery facilitated by the LPP-PBA system reduce systemic toxicity—a prevalent concern in cancer therapies—thereby enhancing patient safety profiles.
Supporting this innovative research, funding was provided by the National Research Foundation of Korea (NRF) under the Ministry of Science and ICT, alongside the Ministry of Trade, Industry and Resources (MOTIR) through the ITECH R&D Program and Korea Evaluation Institute of Industrial Technology (KEIT). Such collaborative financial backing underscores global recognition of the importance and potential clinical impact of this universal immunotherapy platform.
From a technological perspective, the development of the LPP-PBA delivery system represents an engineering feat. Phenylboronic acid modification endows the lipopolyplex with precise tumor-homing capabilities by exploiting the unique glycosylation profiles of cancer cells. This level of specificity addresses a long-standing challenge in gene delivery: efficient and selective transfection of malignant cells in vivo without affecting normal tissues. Such targeted delivery is paramount in the successful clinical translation of gene-based immunotherapies.
Further preclinical evaluation showcased robust immune system activation post treatment. NK cells, equipped with Fc receptors, rapidly recognized and destroyed Fc-expressing tumor cells and concurrently elicited an adaptive immune response, as evidenced by increased antigen presentation and T-cell activation markers. This phenomenon suggests that the Univody platform not only mediates direct tumor eradication but may also induce long-lasting immunological memory, potentially preventing tumor relapse.
Importantly, the universal nature of the system means it is not restricted by tumor type or antigen expression, enabling its application in tumors previously deemed “immune cold” or refractory to immunotherapeutic modalities. This feature is particularly relevant for aggressive cancers such as melanoma and triple-negative breast cancer, which often exhibit resistance to current treatments. The versatility of Univody thus opens avenues for combinatory regimens with other therapies, including checkpoint inhibitors and chemotherapeutics.
Looking forward, translational research efforts aim to optimize the LPP-PBA delivery vehicle’s pharmacodynamics and scale up genetic construct production for clinical assessment. Further animal studies and eventual human clinical trials are poised to verify safety, dosing regimens, and efficacy across multiple cancer types. The potential to customize and adapt this platform heralds a new era in cancer immunotherapy where universal applicability and precise immune engagement converge.
In conclusion, the Univody platform developed by the POSTECH and UCLA teams represents a groundbreaking advancement in cancer immunotherapy by genetically engineering tumor cells to display antibody Fc fragments, thereby overcoming limitations posed by tumor antigen heterogeneity. Coupled with an innovative targeted delivery system, this strategy triggers potent immune cell-mediated elimination of tumors and holds promise for broad clinical applications across diverse cancer typologies. This transformative approach could redefine therapeutic strategies and significantly improve outcomes for patients facing challenging malignancies.
Subject of Research: Cancer immunotherapy; genetic engineering of tumor cells for antibody fragment display; universal antibody technology.
Article Title: In Situ Tumor Surface Modification with Antibody Fragments for Antigen-Independent Versatile Cancer Immunotherapy
News Publication Date: 24-Jul-2025
Web References: http://dx.doi.org/10.1021/acsnano.5c08128
Image Credits: POSTECH
Keywords: Cancer immunotherapy, universal antibody, antibody fragments, antigen-independent, tumor surface modification, natural killer cells, LPP-PBA delivery system, phenylboronic acid, gene delivery, tumor targeting, immunotherapy, nanomedicine
