CAR T cell therapy beyond cancer: current status, challenges and future prospects

In vivo CAR‑T therapy: recent progress and future directions

Emerging target antigen landscape for CAR T-cell therapy in solid tumors: current advances and future directions

Reprogramming CAR-T Cell Therapy for Solid Tumors: Combination Strategies to Overcome Resistance

The biological mechanisms underlying resistance to CAR-T therapy in solid tumors are examined and emerging combination strategies designed to enhance tumor recognition, trafficking, persistence, and antitumor activity are critically evaluated.

Integrated Engineering of CAR‐T Cells for Solid Tumours

This review examines the transition from single‐axis engineering to an integrated framework that addresses hurdles in sequence, and delineates how next‐generation CAR‐T cells are designed for precise spatiotemporal activation through logic‐gated and pharmacologically regulatable receptors, while being reinforced by metabolic and epigenetic reprogramming to resist TME‐driven exhaustion.

Immune checkpoint blockade enhances CD4 effector function to control persistent viral infection 2267612

T cell exhaustion, a defining hallmark of chronic viral infections and cancer, is characterized by the progressive loss of effector function and sustained expression of inhibitory receptors on T cells. Although immune checkpoint blockade (ICB) therapies, such as PD-1 inhibition, can transiently reinvigorate subsets of exhausted CD8+ T cells, their efficacy remains constrained by the limited pool of self-renewing, progenitor-like TCF1+ CXCR5+ CD8+ T cells. We have previously demonstrated that B cell—derived IL-27 signaling is necessary for the expansion and maintenance of this progenitor-like population during chronic infection. Using an IL-27 receptor deficient mouse model, we reveal a previously unrecognized mechanism by which PD-1 blockade mediates viral clearance. We demonstrate that PD-1 inhibition enhances CD4+ T cell function, specifically through increased IL-21 production from T follicular helper (Tfh) cells which promotes both humoral and cytotoxic antiviral responses. Our findings identify a novel IL-27 independent CD4+ T cell axis through which checkpoint blockade controls persistent viremia. To determine the impact of checkpoint inhibition on persistent viral infection, IL-27 receptor—deficient mice were infected with chronic lymphocytic choriomeningitis virus (LCMV clone 13) and treated with PD-1 blocking antibodies. We used flow cytometry and viral titers to evaluate CD4+ and CD8+ T cell subsets, the importance of IL-21, and persistent viral clearance. PD-1 blockade restored antiviral immunity in IL-27 receptor—deficient mice and resulted in enhanced CD4+ T cell function. We saw increased IL-21 production from T follicular helper cells that led to higher cytotoxic and humoral antiviral responses. Our studies reveal that PD-1 blockade can drive persistent viral clearance through an IL-27—independent mechanism that involves IL-21—producing CD4+ T cells. N/A Viral Immunology (VIR)

Mechanisms, optimization strategies, and salvage options for CAR-T cell therapy

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment landscape for relapsed or refractory hematologic malignancies, producing high remission rates in otherwise treatment-resistant patients. However, primary resistance and disease relapse remain common, particularly in solid tumors, limiting long-term benefit and broader clinical applicability. As the population of patients failing therapy grows, there is an urgent need for an integrated understanding of resistance mechanisms and a structured approach to salvage therapy. This review proposes a conceptual “Why-How-What if” framework to navigate the complexities of treatment failure. We first address “Why” therapy fails, identifying multifactorial drivers including tumor-intrinsic factors like antigen loss and immune evasion, T cell-intrinsic dysfunction such as exhaustion and limited persistence, and extrinsic constraints imposed by an immunosuppressive tumor microenvironment. We then explore “How” to enhance efficacy through mechanism-based strategies. These include rational combination approaches with immune checkpoint inhibitors or small molecule inhibitors, and next-generation engineering such as dual-target, armored, and in vivo generated CAR-T cells aimed at overcoming metabolic and physical barriers. Finally, we address the “What if” of treatment failure by summarizing individualized salvage options, for which current clinical evidence is derived predominantly from hematologic malignancies. These strategies range from target-switching and bispecific antibodies to emerging cellular platforms like CAR-natural killer cells and consolidation via allogeneic hematopoietic stem cell transplantation. By integrating mechanisms of failure with evolving optimization and salvage strategies, this framework provides a practical roadmap for clinical and translational progress. Future success will depend on biomarker-guided combinations and the continued diversification of adoptive cell therapy platforms.