Runzhi Chen, Dongmei Yang, Huiting Xu
This retrospective two-patient case series observed one PR and one SD in heavily pretreated MSS mCRC patients with prior ICI failure who received chidamide plus a PD-1 inhibitor (Case 1: primary resistance; Case 2: acquired resistance). As descriptive observations, these findings are hypothesis-generating only and are insufficient to demonstrate reversal of immunotherapy resistance or survival benefit. Prospective biomarker-driven studies are warranted to evaluate epigenetic-immunotherapy combinations in this subgroup.
BACKGROUND: More than 90% of metastatic colorectal cancers (mCRC) are microsatellite-stable (MSS), an immunologically "cold" subtype characterized by low neoantigen burden, impaired antigen presentation, and poor responsiveness to immune checkpoint inhibitors (ICIs). Epigenetic aberrations-including aberrant DNA methylation and histone deacetylation-drive immune evasion in MSS CRC. Histone deacetylase inhibitors (HDACi) can restore major histocompatibility complex class I (MHC-I) expression, reshape the immunosuppressive tumor microenvironment (TME), and synergize with ICIs to enhance antitumor immunity. This retrospective study evaluated chidamide (a selective HDACi) plus a PD-1 inhibitor in two MSS CRC patients with prior ICI progression, with a mechanistic discussion informed by published evidence.
CASE PRESENTATION: Case 1: A 60-year-old woman with BRAF V600E-mutant, right-sided, MSS mCRC received third-line surufatinib plus camrelizumab, with a best response of stable disease (SD) and a progression-free survival (PFS) of 5 months. After subsequent disease progression, fifth-line chidamide plus sintilimab achieved a partial response (PR), with a PFS of 6 months. Case 2: A 43-year-old man with recurrent RAS/BRAF wild-type MSS mCRC received fifth-line surufatinib plus sintilimab (PR, PFS 8.5 months) and, after progression, seventh-line chidamide plus sintilimab plus bevacizumab (SD, PFS 5.5 months). No grade 3-4 AEs occurred.
CONCLUSION: This retrospective two-patient case series observed one PR and one SD in heavily pretreated MSS mCRC patients with prior ICI failure who received chidamide plus a PD-1 inhibitor (Case 1: primary resistance; Case 2: acquired resistance). As descriptive observations, these findings are hypothesis-generating only and are insufficient to demonstrate reversal of immunotherapy resistance or survival benefit. Prospective biomarker-driven studies are warranted to evaluate epigenetic-immunotherapy combinations in this subgroup.