Chimeric antigen receptor T cell (CAR-T) therapy and immune checkpoint inhibitors continued their evolution from hematologic malignancies toward solid tumors, with 2025 bringing significant advances in engineering strategies, combination approaches, and manufacturing innovation [1][2][3][4][5].
Novel engineering approaches emerged to overcome the immunosuppressive tumor microenvironment that has limited CAR-T efficacy in solid cancers. CRISPR-edited CAR-T cells with simultaneous immune checkpoint gene knockout (particularly PD-1) demonstrated enhanced persistence and reduced cytokine release syndrome in preclinical models [1][2]. The development of "off-the-shelf" allogeneic CAR-T cells and in vivo CAR-T generation using CRISPR-loaded functionalized nanocarriers offered scalable, economical alternatives to traditional autologous manufacturing [3].
Combination strategies gained traction, with preclinical and early clinical data supporting synergistic effects when pairing CAR-T therapy with immune checkpoint inhibitors, oncolytic viruses, or CAR-NK cells [2][4]. Artificial intelligence-driven target discovery and synthetic biology approaches aimed to improve tumor specificity while minimizing on-target, off-tumor toxicity [1]. Machine learning systems like SCORPIO demonstrated ability to predict checkpoint inhibitor efficacy using routine blood tests, potentially democratizing access to biomarker-driven treatment selection [5].
Why it matters:
For clinicians: The expansion of CAR-T therapy beyond CD19-targeting for B-cell malignancies toward solid tumors like gastric cancer, liver cancer, and glioma represents a paradigm shift in oncologic care. Combination strategies with checkpoint inhibitors may overcome resistance mechanisms, though managing overlapping toxicities requires specialized expertise. Machine learning prediction tools could enable more personalized immunotherapy selection without requiring expensive genomic testing.
For researchers: Engineering strategies combining CRISPR gene editing, cytokine armoring, and checkpoint disruption offer rational approaches to enhance CAR-T functionality. However, solid tumor penetration, antigen heterogeneity, and the immunosuppressive microenvironment remain formidable challenges requiring innovative solutions. Translating preclinical combination strategies into clinical trials will be essential to realize the full potential of these therapies.
References
- Chen Y, Ren R, Yan L, et al. From Bench to Bedside: Emerging Paradigms in CAR-T Cell Therapy for Solid Malignancies. Adv Sci. 2025;12(40):e05822. doi: 10.1002/advs.202505822
PubMed: https://pubmed.ncbi.nlm.nih.gov/40855662/ - Khan SH, Choi Y, Veena M, Lee JK, Shin DSS. Advances in CAR T cell therapy: antigen selection, modifications, and current trials for solid tumors. Front Immunol. 2025;15:1489827. doi: 10.3389/fimmu.2024.1489827
PubMed: https://pubmed.ncbi.nlm.nih.gov/39835140/ - Saha T, Saha RP, Singh MK, et al. An overview on in-vivo generation of CAR-T cells using CRISPR-loaded functionalized nanocarriers for treating B-cell lineage acute lymphoblastic leukemia. Mol Biol Rep. 2025;52(1):596. doi: 10.1007/s11033-025-10674-1
PubMed: https://pubmed.ncbi.nlm.nih.gov/40515942/ - Ali S, Arshad M, Summer M, et al. Recent developments on checkpoint inhibitors, CAR T cells, and beyond for T cell-based immunotherapeutic strategies against cancer. J Cell Physiol. 2025;31(7):1115-1144. doi: 10.1177/10781552251324896
PubMed: https://pubmed.ncbi.nlm.nih.gov/40152219/ - Yoo SK, Cassini TA, Tinker RJ, et al. Prediction of checkpoint inhibitor immunotherapy efficacy for cancer using routine blood tests and clinical data. Nat Med. 2025;31(3):869-880. doi: 10.1038/s41591-024-03398-5
PubMed: https://pubmed.ncbi.nlm.nih.gov/39762425/