Multi-omic paired analysis reveals chemotherapy-associated immunosuppressive changes and therapeutic insights in recurrent endometrial carcinoma

Combination chemotherapy with immune checkpoint blockade has reshaped the treatment landscape for recurrent endometrial carcinoma (EC). However, subgroup analyses have demonstrated limited efficacy in patients previously treated with platinum-based adjuvant chemotherapy. To investigate how prior adjuvant chemotherapy affects the tumor microenvironment (TME) at recurrence, we analyzed 32 matched primary–recurrent EC pairs by performing multi-omic profiling in 20 pairs and multiplex immunohistochemistry (mIHC) in all cases. Recurrent tumors with prior platinum-based adjuvant chemotherapy exhibited increased variant allele frequencies of mutations in MYC signaling-related genes, with enrichment of glycolysis, regulatory T (Treg) cells, and M2 macrophage polarization. mIHC demonstrated increased Treg-cell infiltration and the M2/M1 macrophage ratio in recurrent tumors compared with matched primary tumors. Moreover, progression-free survival after recurrence correlated more strongly with the TME of recurrent tumors than with that of the primary tumors. Platinum-based adjuvant chemotherapy is associated with the emergence of immunosuppressive TME features in recurrent EC.