MSI-H/dMMR

At the same time, in the tissue of atypical hyperplasia and adenocarcinoma, this mutation led to an explosive accumulation of oncogenic genetic variants. This observation indicates role of mutation in the POLE gene as an early driver of carcinogenesis and emphasizes the importance of its determination in atypical endometrial proliferations.

The established biomarkers PD-L1, TMB, and microsatellite instability-high/deficient mismatch repair inform ICI use in clinical practice but have important limitations. Multiple investigational biomarkers show promise in refining patient selection and optimizing therapy. Moving forward, increased assay harmonization, prospective validation, and standardized parameters may improve performance. Composite models integrating complementary signals across domains may further individualize treatment and lead to an era of personalized cancer immunotherapy.

P2, N=18, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed

We also highlight clinically relevant biomarkers, including MSI/MMR status, tumor mutational burden, immune contexture, Immunoscore, circulating tumor DNA, microbiome profiles, and spatial or AI-assisted multi-marker models. This review summarizes emerging strategies to enhance therapeutic efficacy in CRC and maps each modality to the tumor-intrinsic or tumor-extrinsic resistance barriers it is most likely to overcome.

Specifically, we identified GDF15 as key tumor-cell ligands that may interact with precursor CAFs to promote POSTN+ CAF differentiation. Our findings uncover a stromal mechanism of ICB resistance in dMMR/MSI-H CRC mediated by POSTN+ CAFs and highlight novel therapeutic strategies to enhance immunotherapy efficacy.

These findings highlight the heterogeneity of immune checkpoint expression patterns and provide preliminary, hypothesis-generating insights into variability in response to PD-1/PD-L1 blockade.

Due to limited germline and epigenetic data, MSI-H tumors could not be classified as Lynch-associated or sporadic. Overall, MSI-H and MSS CRCs in the Chinese population demonstrate distinct molecular landscapes in terms of TMB, HRD, EBV status, and driver gene alterations, underscoring the molecular heterogeneity of MSI-H CRC and the need for future studies integrating germline and epigenetic data to refine subtype classification.

This study provides a comprehensive single-cell atlas of CD27+ cytotoxic T cell heterogeneity in CRC, revealing exhaustion dynamics, regulatory networks, and spatial organization patterns. Our findings highlight the differential immunogenic capacity between MSI-H and MSS tumors and identify potential therapeutic targets for reversing T cell exhaustion in colorectal cancer.

We present a case of a 68-year-old woman with metastatic functional PanNET (VIPoma) who developed a treatment-associated hypermutated, microsatellite instability-high (MSIhigh) phenotype following capecitabine-temozolomide (CAPTEM) therapy. Treatment with pembrolizumab resulted in a robust clinical, biochemical, and radiographic response. This case highlights dynamic genomic evolution in PanNETs and underscores the importance of serial molecular profiling in guiding therapeutic decisions.

P1, N=18, Recruiting, Joint Biosciences Ltd.

This case demonstrates the diagnostic value of USG-FNAC as a reliable and safe method for confirming metastasis in anatomically challenging locations. Additionally, it emphasises the importance of incorporating molecular profiling and recognising histological features such as squamous differentiation and MELF patterns as markers of aggressive behaviour in a subset of low-to-intermediate grade EC.

This case highlights the paradoxical response to ICIs in ICC, demonstrating that MSI-H status does not preclude HPD. Further investigation of the tumor immune microenvironment is warranted.