Can OX40 (CD134) co-stimulatory signaling become a new strategy to overcome resistance in tumor immunotherapy?

I. Why Do We Need Next-Generation Immune Checkpoint Therapies Beyond PD-1/CTLA-4?

Immune checkpoint inhibitors (ICBs) targeting PD-1/PD-L1 and CTLA-4 have revolutionized the treatment landscape for various cancers. However, their clinical application still faces two core challenges: primary resistance (initial ineffectiveness in some patients) and acquired resistance (treatment failure after a period of time). The resistance mechanisms are complex, involving defects in tumor antigen presentation, infiltration of immunosuppressive cells (such as Tregs and MDSCs), and multiple inhibitory signaling networks in the tumor microenvironment (TME). Therefore, developing next-generation therapies that can reshape the TME and directly activate anti-tumor immune responses is key to overcoming current treatment bottlenecks. Among these, targeting co-stimulatory signals, especially members of the tumor necrosis factor receptor superfamily (TNFRSF) such as OX40 (CD134), is considered a highly promising approach.

II. How Does OX40 (CD134) Regulate T Cell Immune Responses?

OX40 (also known as CD134) is a type I transmembrane glycoprotein primarily expressed on activated T cells (including effector T cells and regulatory T cells, Tregs) and belongs to the TNFRSF. Its ligand, OX40L, is mainly expressed on antigen-presenting cells. OX40 is not the initiation switch for T cell activation but provides a crucial "second signal" or "co-stimulatory signal" after the T cell receptor (TCR) receives the primary antigen signal.

The biological functions of OX40 are primarily reflected in:

1. Promoting T Cell Survival and Expansion: OX40 signaling activates multiple downstream pathways, including NF-κB, PI3K/AKT, and NFAT, upregulating anti-apoptotic proteins (such as Bcl-2 and Bcl-xL) and cell cycle proteins, effectively preventing activated T cell apoptosis and promoting clonal expansion, thereby forming a robust and long-lasting pool of effector T cells.

2. Inhibiting Regulatory T Cell Function: OX40 signaling can suppress the expression of the key transcription factor Foxp3 in Treg cells, weakening their immunosuppressive function and potentially even inducing their exhaustion, thereby lifting their suppression of effector T cells.

3. Enhancing T Cell Effector Function: OX40 co-stimulation can improve the ability of effector T cells (especially CD4+ T cells) to produce cytokines (such as IL-2 and IFN-γ) and promote their migration and infiltration into the TME.

Thus, unlike PD-1 and other checkpoint inhibitors that "release the brakes," targeting OX40 aims to "step on the gas," actively and powerfully driving T cell activation, expansion, and functional maintenance, particularly in tumor microenvironments where T cell function is suppressed or exhausted.

                  III. What Potential Has CD134 (OX40) Antibody Shown in Preclinical Studies?

In various preclinical tumor models, agonistic CD134 (OX40) antibodies have demonstrated significant anti-tumor activity. Their mechanism of action not only involves direct activation of effector T cells but also includes modulation of immunosuppressive components in the TME:

- Single-Agent Activity: In certain lymphoma and solid tumor models, anti-OX40 monotherapy can effectively induce tumor regression and establish long-term immune memory.

- Synergistic Effects in Combination Therapy: Anti-OX40 antibodies show great promise when combined with existing therapies. For example, combining with PD-1/PD-L1 inhibitors can simultaneously provide "co-stimulation" (OX40) and relieve "co-inhibition" (PD-1), producing powerful synergistic anti-tumor effects and significantly improving response rates and survival. Combination with chemotherapy, radiotherapy, or other immune agonists (such as TLR agonists) can also enhance efficacy by promoting tumor antigen release and strengthening immune responses.

- Overcoming Treg-Mediated Suppression: Studies show that anti-OX40 antibodies may selectively deplete or inhibit OX40-high-expressing Treg cells in the TME without affecting effector T cells, effectively reversing the immunosuppressive microenvironment.

Notably, the timing of combination therapy administration may impact final efficacy. Some studies suggest that in certain models, administering OX40 agonists first to initiate and expand T cells, followed by PD-1 inhibitors to reverse their exhaustion state, may yield better results than simultaneous administration.

IV. Can OX40 Expression Serve as a Biomarker for Predicting Immunotherapy Efficacy?

Preliminary clinical observations suggest that OX40 may have potential as a biomarker. In studies of ovarian cancer, colon cancer, and others, high levels of OX40 expression in tumor-infiltrating lymphocytes (TILs) correlate with better sensitivity to chemotherapy, longer recurrence-free survival, and overall survival. In some patients receiving immune checkpoint inhibitors, the proportion of OX40+ T cells in peripheral blood or tumors before treatment also positively correlates with better treatment responses and survival benefits. These data support OX40 as an indicator of immune activity, but its value as an independent predictive biomarker still requires further validation in prospective large-sample studies.

V. What Role Does CD134 (OX40) Antibody Play in Research and Application?

In advancing OX40-targeted therapies from the lab to the clinic, high-quality, functionally defined CD134 (OX40) antibodies are indispensable core tools:

1. Mechanism Research and Target Validation: These antibodies are key probes for studying OX40's role in T cell activation, survival, differentiation, and function in the TME, used in flow cytometry for expression detection, immunohistochemistry for tissue localization, and functional validation through agonistic or blocking experiments.

2. Drug Screening and Optimization: In developing therapeutic OX40 agonistic antibodies, candidate molecule screening, affinity determination, and functional activity assessment (such as inducing T cell proliferation and cytokine release) rely on comparisons and competition experiments with standard CD134 antibodies.

3. Preclinical Pharmacodynamic Evaluation: In humanized OX40 mouse models or syngeneic tumor models, using candidate anti-human OX40 antibodies for in vivo efficacy experiments is a critical step in assessing their anti-tumor activity, optimal dosing regimens, and synergistic effects with other therapies (such as anti-PD-1 antibodies).

4. Companion Diagnostic Development: As OX40-targeted therapies enter clinical trials, developing companion diagnostic reagents to detect OX40 expression levels in patient tumors or blood will depend on highly specific CD134 detection antibodies to screen potential beneficiary populations.

VI. Summary and Outlook

OX40 (CD134), as a key T cell co-stimulatory receptor, offers a new mechanism of action and combination strategies to overcome resistance to current immune checkpoint inhibitors. Agonistic CD134 (OX40) antibodies can revitalize anti-tumor immunity in the TME by directly activating effector T cells and inhibiting Treg function. Although their single-agent activity has not yet fully emerged in early clinical trials, combination regimens with PD-1/PD-L1 inhibitors and others have shown encouraging prospects in preclinical and early clinical studies. In the future, by optimizing antibody design (such as enhancing Fc effector function and developing bispecific antibodies), exploring optimal combination regimens and administration timing, and using tools like CD134 antibodies to identify reliable predictive biomarkers, OX40-targeted therapies are expected to become a vital component of the tumor immunotherapy arsenal, offering hope to more patients.

VII. Which Manufacturers Provide CD134 Antibodies?

Hangzhou Start Biotech Co., Ltd. has independently developed the "Mouse Anti-Human CD134 Antibody" (product name: Mouse Anti-Human CD134 Antibody (S-R589), catalog number: S0B5119), a high-specificity, high-affinity, and exceptionally stable detection tool for T cell co-stimulatory receptors. This product can accurately recognize human CD134 (OX40) protein and holds significant application value in T cell activation research, tumor immunotherapy, and exploration of autoimmune disease mechanisms.

Professional Technical Support: We provide comprehensive product technical documentation, including complete specificity validation data, experimental protocols, and professional technical support, fully assisting customers in advancing research in T cell immunity and tumor immunotherapy.

Hangzhou Start Biotech Co., Ltd. is committed to providing high-quality, high-value biological reagents and solutions to global innovative pharmaceutical companies and research institutions. For more details about the "Mouse Anti-Human CD134 Antibody" (catalog number S0B5119) or to request sample testing, please contact us.

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