Emerging therapeutic opportunities targeting nonclassical MHC-I molecules.

CD74 in hematological malignancies: from MHC chaperone to therapeutic target.

CD74, originally known as the invariant chain of Major Histocompatibility Complex Class II Molecules (MHC class II), has now been acknowledged as a versatile signaling nexus and a universal lymphoma antigen. It has a pivotal role in the maturation, stimulation, and viability of various immune cells, such as B cells, T cells, Regulatory T Cells (Tregs), monocytes, and macrophages. It is extensively and significantly expressed in a variety of hematologic cancers, encompassing acute and chronic leukemias, lymphomas, and multiple myeloma. Given its expression pattern, along with its swift internalization and limited expression in most normal tissues, CD74 emerges as a promising target for a wide array of therapeutic approaches like antibody-drug conjugates (ADCs), bispecific antibodies, and Chimeric Antigen Receptor T-cell (CAR-T) therapy. However, the downstream signaling network of CD74 is highly context-dependent, playing a dual role in physiological immune regulation and pathological pro-cancer survival.

Immunotherapeutic control of MHC I-heterogeneous tumors to minimize therapy resistance 2307892

The anti-tumor activity of CD8 T cells, which recognize MHC I-presented tumor antigens, is enhanced by blocking checkpoint receptors. Longitudinal tumor biopsies from patients with acquired resistance to anti-PD-1 therapy often reveal genetic deficiencies in antigen presentation or MHC I expression. The role of CD8 T cells in selecting for MHC I-deficiency has been inferred but never demonstrated. Defining causes of MHC I loss and approaches to prevent it are essential for improving the outcomes of cancer immunotherapy. To define immune cells responsible for selecting for outgrowth of MHC I-deficient tumors, we developed MHC I-mixed tumor models, applied immunotherapies, and depleted immune subsets. Tumor growth and composition (MHC I+ vs MHC I-) were determined. PD-1 blockade immunotherapy was poorly effective in mixed MHC I+/MHC I- tumor models and exerted potent selection mediated by CD8+ T cells for outgrowth of MHC I- cells. In contrast, IL-2 “superkines”, alone or in combination with STING agonists, were more effective and prevented outgrowth of MHC I- tumor cells in a manner dependent on multiple immune cell types. An alternative therapeutic approach in which Treg cells are depleted intratumorally also suppressed growth of both MHC I+ and MHC I- tumor cells, in this case largely independently of CD8 T cells. We demonstrated for the first time in a controlled setting with mixed MHC I+/- tumors that anti-PD-1 therapy selects for outgrowth of MHC I-deficient tumor cells, dependent on CD8 T cells. Outgrowth of MHC I-deficient cells was minimized and mixed tumors were better controlled with IL-2 “superkine” therapy, alone or in combination with a STING agonist, and intratumoral Treg depletion. Tumor control in those cases was mediated by multiple effector cell types. Thus, immunotherapies that drive mixed responses of CD8+ and CD4+ T cells and NK cells have the potential to minimize acquired resistance resulting from MHC I loss. NIH: R01CA270790 Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Superantigens in Cancer Immunotherapy: Mechanisms, Engineering Strategies, and Therapeutic Potential

Cancer immunotherapy has reshaped modern oncology by enabling the immune system to recognize and eliminate malignant cells. However, many solid tumors still respond poorly because of weak T‐cell activation and an immunosuppressive tumor microenvironment. Bacterial superantigens (SAgs) represent a unique class of immunomodulatory proteins capable of overcoming these limitations through direct activation of large T‐cell populations. Unlike conventional antigens, superantigens bypass classical antigen processing by simultaneously binding major histocompatibility complex class II molecules and T‐cell receptor Vβ domains, triggering rapid cytokine release and extensive immune activation. Although this potent mechanism has historically been associated with severe systemic toxicity, recent advances in protein engineering and targeted delivery have renewed interest in their therapeutic potential. This review discusses the structural and immunological basis of superantigen activity and highlights emerging strategies designed to improve tumor specificity and safety, including engineered low‐toxicity variants, antibody‐superantigen fusion proteins, nanoparticle‐based delivery systems, and tumor‐targeted constructs. We further examine how superantigens reshape the tumor microenvironment and synergize with immune checkpoint blockade, adoptive cell therapies, and other T‐cell‐redirecting approaches. Together, these advances position engineered superantigens as promising immune‐amplifying platforms with the potential to complement existing cancer immunotherapies and improve responses in poorly immunogenic tumors.

Targeting immune checkpoint B7-H6 in cancer immunotherapy

Natural killer (NK) cells are central mediators of antitumor immunity and possess the unique ability to recognize and eliminate malignant cells independently of major histocompatibility complex (MHC) restriction. Compared with T-cell-based approaches, NK-cell immunotherapies generally exhibit a more favorable safety profile, highlighting their growing therapeutic potential in oncology. Among the ligands that regulate NK-cell activity, B7-H6 has emerged as a particularly attractive target because of its highly restricted expression in normal tissues and frequent upregulation across diverse malignancies. Initially identified as a ligand for the activating NK-cell receptor NKp30, B7-H6 is now recognized as a multifunctional molecule with roles extending beyond immune recognition. Accumulating preclinical evidence suggests that B7-H6 may contribute to tumor progression by regulating signaling pathways involved in proliferation, survival, migration, invasion, and immune evasion. Furthermore, the existence of soluble B7-H6 adds an additional layer of biological complexity and may influence both NK-cell function and therapeutic responsiveness. In this review, we summarize current knowledge regarding the regulation, expression patterns, and biological functions of B7-H6, with particular emphasis on its dual roles in tumor immunology and cancer cell biology. We discuss the emerging significance of soluble B7-H6, evaluate the current landscape of B7-H6-targeted therapeutic strategies, including bispecific engagers and cellular immunotherapies, and highlight key translational challenges that may influence clinical development. Collectively, current findings position B7-H6 as a promising immuno-oncologic target at the intersection of immune surveillance, immune escape, and malignant progression, warranting continued investigation as a next-generation therapeutic axis in cancer immunotherapy.

Examination of Class I HLA-Fc Fusion Proteins in Targeting Cognate Antibody-Producing Cells.

Structural Foundation of CTLA-4 antibodies: Emerging Platforms for Next-generation Cancer Immunotherapy.

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a critical immune checkpoint receptor that restrains T-cell activation and maintains peripheral tolerance by outcompeting CD28 for shared B7 ligands on antigen-presenting cells (APC). Dysregulation of CTLA-4 signaling is implicated in autoimmune pathologies, lymphoproliferative disorders, and tumor immune evasion, underscoring its broad therapeutic relevance. As the first checkpoint target validated in cancer immunotherapy, CTLA-4 has been extensively characterized at the structural level. High-resolution crystallographic studies have revealed how its extracellular IgV-like domain, MYPPPY ligand-binding motif, and cytoplasmic trafficking machinery collectively encode inhibitory function. Therapeutic antibodies targeting CTLA-4, including the FDA-approved agents ipilimumab and tremelimumab, achieve checkpoint blockade through steric occlusion of the B7-binding interface, inhibition of transendocytosis, and Fc-mediated regulatory T-cell depletion. Despite shared mechanisms, these agents differ markedly in effector function and toxicity profile. Other antibodies, including JS007, have entered clinical evaluation, while structurally characterized agents such as mipi.4 and KN044 provide preclinical and translational insights. Emerging engineering strategies, Fc-optimized variants, tumor-activated prodrug formats, bispecific antibodies, and alternative scaffolds such as nanobodies and DARPins are now translating these structural insights into next-generation therapeutics with improved selectivity and reduced immune-related adverse events. By connecting atomic-level receptor recognition to clinical outcome, this review provides a mechanistic foundation for the rational design of next-generation CTLA-4 therapeutics with improved efficacy and reduced immune-related toxicity.