The field of oncology has been revolutionized by the introduction of immune checkpoint inhibitors, with anti-PD-1 therapies offering durable responses in various cancers. However, one of the major obstacles remains resistance—both intrinsic and acquired—to these therapies. Genetic contexts, such as EGFR exon 19 deletions in non-small cell lung cancer (NSCLC), often lead to immunosuppressive tumor microenvironments (TMEs) characterized by regulatory T cell (Treg) accumulation and elevated TGF-β signaling. This suppresses cytotoxic T lymphocyte activity, counteracting the efficacy of immune checkpoint blockade. Despite promising preclinical findings, direct targeting of TGF-β signaling has not yet achieved clinical success, and no FDA-approved inhibitors are available. As a result, new immuno-modulating modalities are being researched to enhance the specificity, efficacy, and longevity of anti-tumor responses.

This Research Topic aims to spotlight innovative advances in modality-based immunotherapy that are designed to overcome resistance to conventional immune checkpoint blockades. We seek comprehensive investigations of engineered biological agents, such as bispecific T cell engagers, immunocytokines, fusion proteins, antibody-drug conjugates, and CAR-T cell therapies. Of special interest are modalities that focus on neutralizing immunosuppressive signaling, like TGF-β, boosting effector T cell tumor infiltration, or enhancing T cell activation and priming. By integrating concepts from molecular biology, immunoengineering, and translational immunology, we aim to foster an interdisciplinary understanding of how targeted therapeutic designs can redefine the landscape of cancer immunotherapy.

To gather further insights in enhancing anti-tumor immune responses, we welcome articles addressing, but not limited to, the following themes:

-Development and application of T cell engagers, including bispecific or trispecific antibodies
-Design and efficacy of immunocytokines and fusion cytokine therapies like Fc-IL-22 or IL-2 variants
-Drug-conjugated immune checkpoint inhibitors aimed at enhancing precision
-Cutting-edge strategies targeting or neutralizing TGF-β signaling pathways
-Innovations in CAR-T and TCR-engineered T cell therapies, especially in solid tumors

We invite contributions across Original Research, Reviews, Mini-Reviews, Perspectives, Brief Research Reports, and Opinions to share mechanistic insights and trial findings. This Research Topic aspires to be a timely and influential resource for developing next-generation approaches in anti-tumor immunity

The Topic Editors declare no Conflicts of Interest

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Modality-Based Medicine in Anti-Tumor Immunity: Overcoming Resistance and Enhancing Immune Precision