Immune Checkpoint Inhibition in Endometrial Carcinoma

Endometrial carcinoma has emerged as a leading candidate for immune checkpoint blockade owing to its diverse molecular subtypes and frequent mismatch repair deficiency. Tumours harbouring POLE exonuclease‐domain mutations or microsatellite instability accumulate high neoantigen loads, driving robust infiltration by CD8+ T cells and upregulation of checkpoint molecules such as PD-1 and PD-L1. Therapeutic antibodies against PD-1 (including pembrolizumab and dostarlimab) have gained regulatory approval for advanced or recurrent mismatch repair-deficient disease, marking a paradigm shift for patients with limited options. Beyond monotherapy, combination regimens pairing checkpoint inhibitors with chemotherapy, radiotherapy or angiogenesis inhibitors are under active investigation to overcome primary and acquired resistance. Central to improving response rates is the identification of predictive biomarkers—tumour mutational burden, PD-L1 expression and signatures of an inflamed microenvironment have all shown promise. At the same time, mechanisms of immune evasion including regulatory T cell expansion, myeloid-derived suppressor cell recruitment and metabolic alterations pose challenges to durable efficacy. Ongoing research seeks to integrate molecular classification, immune profiling and real-world clinical data to personalise checkpoint inhibition strategies across the full spectrum of endometrial carcinoma.

Research from Nature Portfolio

Recent large‐scale sequencing analyses have delineated the landscape of tumour mutational burden across endometrial carcinoma subtypes, revealing that POLE-mutant and microsatellite-unstable cancers exhibit the highest mutation rates and neoantigen loads. Patterns of co-occurring alterations in genes such as PTEN, ARID1A and PIK3CA correlate with elevated immune infiltration and may refine patient selection for checkpoint blockade. Importantly, this work has provided a quantitative framework for integrating mutational burden with molecular classification, laying the groundwork for prospective biomarker-driven trials of PD-1/PD-L1 inhibitors.

Immune Checkpoint Inhibition in Endometrial Carcinoma publication trend

The graph below shows the total number of articles in immune checkpoint inhibition in endometrial carcinoma across all publications each year (not limited to Nature Index journals).

Technical terms

Immune checkpoint: A regulatory pathway in T cells that modulates immune responses to prevent autoimmunity, often exploited by tumours to evade detection.

PD-1 (Programmed Death-1): An inhibitory receptor on activated T cells that limits antitumour immunity when engaged by its ligands.

PD-L1 (Programmed Death-Ligand 1): A ligand expressed on tumour or immune cells that binds PD-1 to suppress T cell activity.

CTLA-4 (Cytotoxic T-Lymphocyte-Associated Protein 4): An inhibitory receptor on T cells that competes with costimulatory molecules to dampen early immune activation.

Mismatch repair deficiency (dMMR): Loss of DNA repair proteins leading to microsatellite instability and high mutational burden.

Microsatellite instability (MSI): A hypermutator phenotype resulting from defective DNA mismatch repair, associated with abundant neoantigens.

Tumour mutational burden (TMB): The total number of somatic mutations per coding area of a tumour genome, used as a surrogate for neoantigen load.

Tumour microenvironment: The cellular milieu surrounding a tumour, including immune cells, stromal elements and signalling factors that influence therapy response.

References

1. Promise of dostarlimab in cancer therapy: Advancements and cross-talk considerations. Drug Discovery Today (2023).
2. Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition. OncoImmunology (2017).
3. Mapping the immunosuppressive environment in uterine tumors: implications for immunotherapy. Cancer Immunology, Immunotherapy (2014).
4. PD-L1 Expression in Endometrial Cancer and Its Association with Clinicopathological Features: A Systematic Review and Meta-Analysis. Cancers (2022).