CD155 has emerged as a critical immune checkpoint

The gap

Evidence profile

Stated in the future work section of the source papers, classified as general, spanning 3 journals.

Supporting evidence — 3 representative gaps

• Cell-based cancer immunotherapy: milestones, mechanistic insights, and emerging therapeutic directions (2026) · Acta Pharmacologica Sinica · doi

  Cell-based immunotherapies have emerged as a central component of contemporary oncology by enabling therapeutic mechanisms that are difficult to achieve with conventional modalities, functional adaptability within including in vivo expansion, dynamic tumor ecosystems, and the potential for durable immune surveillance. The clinical success of CAR T-cell therapy in hematologic malignancies has validated this paradigm and catalyzed the development of a broader spectrum of cellular tumorplatforms, infiltrating lymphocytes, NK cell–based therapies, dendritic cell vaccines, and macrophage-directed strategies [121–123]. Collectively, these approaches expand the scope of precision immunooncology by engaging complementary immune functions, including antigen-specific cytotoxicity, innate effector activity, antigen presentation and repertoire shaping, and active modulation of the tumor microenvironment. encompassing TCR–engineered T Despite this progress, the principal limitations of the field are now well defined. Antigen escape and heterogeneous target expression continue to compromise response durability, particularly for single-antigen strategies. In solid tumors, immune exclusion, suppressive myeloid programs, metabolic constraints, and physical barriers collectively limit cellular trafficking, persistence, and effector function, even in the presence of tumor- In parallel, manufacturing remains reactive immune cells. both a biological and logistical bottleneck; variability in starting material, prolonged vein-to-vein timelines, and high production costs restrict scalability and broad clinical access [125, 126]. These challenges indicate that future advances will depend less on incremental refinement of individual platforms and more on integrated strategies that simultaneously address target recognition, cellular fitness, tumor accessibility, and safety. Several development priorities are likely to shape the next phase of cellular immunotherapy. Multiplex targeting and logic-gated designs provide promising solutions to antigen escape while improving on-target specificity. Cell-state engineering—supported by optimized manufacturing conditions, epigenetic and metabolic conditioning, and precise genome editing—offers a pathway to enhanced persistence and resistance to exhaustion [128, 129]. Off-the-shelf approaches, including allogeneic donor–derived products and iPSC–based platforms, have the potential to reduce production timelines and improve scalability, provided that immune rejection and product consistency can be effectively controlled [53, 130, 131]. rational combination strategies are increasingly In addition, essential; likely require coordinated interventions integrate immune improved trafficking, and tumor microenvironment priming, modulation while maintaining an acceptable therapeutic index.

  generalstated in future workevidence 5/5
  Keywords: tumor immune cell antigen cellular strategies based platforms target oncology therapeutic including potential durable clinical
• Regulatory T cells in the bladder cancer tumor microenvironment: mechanisms of immune suppression and therapeutic opportunities (2026) · Frontiers in Molecular Biosciences · doi

  Considering their immunosuppressive roles in the BC TME, Tregs represent potential therapeutic targets. However, their systemic depletion can compromise immune tolerance and lead to immune-related toxicities. Therefore, therapeutic strategies should aim to selectively modulate tumor-infiltrating Tregs directly involved in local immune suppression rather than broadly eliminating Tregs in peripheral tissues (Tay et al., 2023). Among potential targets, CCR8 is a promising marker of highly suppressive tumor-infiltrating Tregs. From a therapeutic perspective, CCR8 is appealing as it may facilitate relatively selective targeting of intratumoral Tregs while preserving peripheral Tregs, which are crucial for systemic immune tolerance. Preclinical and translational evidence suggests that CCR8 blockade destabilizes intratumoral Tregs and enhances antitumor immunity in MIBC (Wang et al., 2020), suggesting that CCR8-positive Tregs contribute immunosuppressive niche. Experimental to maintaining an studies in other tumor models have also shown that selective depletion of CCR8-positive tumor-infiltrating Tregs enhances CD8-positive T cell responses and synergizes with PD-1 blockade (Van Damme et al., 2021; Kidani et al., 2022). Additional checkpoint molecules expressed by tumor-infiltrating Tregs, including cytotoxic T-lymphocyte-associated protein 4, PD-1, T cell immunoreceptor with Ig and ITIM domains, and possibly lymphocyte activation gene-3, may also contribute to immunosuppressive signaling; however, their relevance as selective Treg-directed targets in BC remains investigational (Tay et al., 2023). CCR4 may also be a relevant chemokine receptor involved in Treg recruitment in BC. The C-C motif chemokine ligand 17–CCR4 axis promotes Treg accumulation, whereas CCR4 blockade reduces Treg infiltration and prolongs survival in a canine spontaneous BC model. CCR4- positive Tregs have also been observed in human BC tissues, suggesting that this pathway warrants further investigation (Maeda et al., 2019). However, CCR4 is not specific to tumor- infiltrating Tregs and may also be expressed by other T cell subsets. Therefore, CCR4-directed approaches should be considered as potential strategies to modulate Treg recruitment and trafficking rather than as established selective Treg-targeted therapies for human BC. Overall, selective Treg targeting should be viewed as a strategy for remodeling the bladder TME rather than merely depleting Tregs (Figure 2B). Such approaches may be particularly beneficial when combined with therapies that activate antitumor immunity, including BCG and immune checkpoint blockade therapies. Although not designed as a Treg-targeted therapy, a recent phase 3 trial combining BCG therapy with PD-L1 blockade supports the broader concept that modulation of the immunosuppressive bladder TME enhances existing immunotherapeutic strategies (De Santis et al., 2025).

  generalstated in future workevidence 5/5
  Keywords: tregs treg tumor immune infiltrating selective blockade immunosuppressive positive potential therapeutic targets strategies rather enhances
• The PVR-TIGIT/CD96/CD226 axis: a novel immune checkpoint target in ovarian cancer (2026) · Frontiers in Immunology · doi

  CD155 has emerged as a critical immune checkpoint in ovarian cancer, functioning at the crossroads of immune regulation and tumor progression. By interacting with TIGIT and CD96 while competing with CD226, CD155 orchestrates a complex signaling network that drives T cell exhaustion, NK cell dysfunction, and regulatory T cell expansion, ultimately promoting immune evasion. Its expression on tumor cells, dendritic cells, and macrophages, as well as the presence of soluble isoforms, further contributes to the establishment of an immunosuppressive tumor microenvironment. Therapeutic strategies aimed at disrupting the CD155 axis— whether by blocking inhibitory interactions or restoring CD226- mediated co-stimulation—are under active investigation. Monoclonal antibodies, bispecific constructs, and engineered CAR-T or NK cell therapies have demonstrated encouraging preclinical results and early-phase clinical potential. However, several challenges must be addressed before these approaches can be widely translated into clinical practice. First, the dual role of CD155 as both an inhibitory and activating ligand complicates the design of targeted interventions. Non-selective blockade may unintentionally suppress beneficial CD226 signaling. Second, the regulation of CD155 expression is

  generalstated in future workevidence 3/5
  Keywords: cell immune tumor regulation signaling expression cells inhibitory clinical emerged critical checkpoint ovarian cancer functioning

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