Targeting the tumor immune microenvironment in chordoma: From mechanistic insights to therapeutic breakthroughs

Chordoma is a rare, malignant bone tumor characterized by high local recurrence rates and resistance to conventional therapies. While immunotherapy has emerged as a promising avenue, its clinical efficacy is currently limited by a profoundly immunosuppressive tumor immune microenvironment (TIME). This review systematically elucidates the molecular and cellular mechanisms underpinning the distinct "immune-excluded" phenotype in chordoma. In this architecture, effector T cells are physically sequestered from tumor cells by dense stromal septa, which paradoxically function as hubs for myeloid-T cell interaction rather than simple physical barriers. This immune-excluded architecture is orchestrated through multiple interconnected mechanisms. Cancer-associated fibroblasts (CAFs), particularly inflammatory and stress-related subpopulations, construct physical barriers via extracellular matrix remodeling while secreting chemokines (such as CXCL12) that spatially anchor T cells within the stroma. The transforming growth factor-beta (TGF-β) pathway reinforces this exclusion by suppressing cytotoxic T cell function and impeding tumor infiltration. Intrinsically, chordoma exhibits a low tumor mutational burden and specific genomic alterations-most notably the loss of CDKN2A/B and PBRM1. Furthermore, despite high chromosomal instability (CIN), co-occurring deletions of 9p and 10q silence the cGAS-STING pathway, thereby impairing antigen presentation and immune cell recruitment. The microenvironment is further dominated by M2-polarized tumor-associated macrophages and regulatory T cells, driving effector T cell exhaustion. Clinical evidence indicates that immune checkpoint inhibitors and targeted vaccines yield limited efficacy as monotherapies, highlighting the immune-excluded phenotype and the scarcity of PD-L1 protein expression as primary obstacles. Future therapeutic breakthroughs will require rational combination strategies, including CAR-T cell therapies targeting novel antigens (e.g., B7-H3) and adoptive T-cell transfer, designed to dismantle stromal barriers and exploit systemic anti-tumor immunity.