Objective:To investigate the effect of PIK3CA mutations on the tumor immune microenvironment in Luminal breast cancer and evaluate the potential of Alpelisib-loaded pH-responsive polymer micelles in modulating the tumor immune microenvironment.Methods:PIK3CA mutations in breast cancer were analyzed using bioinformatics tools.A mouse xenograft model of Luminal breast cancer harboring a PIK3CA mutation was established,and alterations in the tumor immune microenvironment were examined using mass cytometry(CyTOF).During the period from August 2004 to December 2008 in Tianjin Medical University Cancer Hospital,tissue biopsies of 62 Luminal breast cancer patients in the BRCA cohort were collected Study the relationship between PIK3CA mutations and tumor immune microenvironment at the organizational level.Alpelisib-loaded polymer micelles(Alpelisib@MSPM)were synthesized,characterized,and evaluated for thera-peutic efficacy in Luminal breast cancer with PIK3CA mutations.Results:PIK3CA is one of the most frequently mutated genes in breast can-cer,with the highest prevalence in Luminal subtypes.CyTOF analysis demonstrated that PIK3CA mutations contribute to a tumor immun-osuppressive microenvironment in xenografts.Multiplex fluorescence immunohistochemistry revealed that PIK3CA-mutated tumors exhib-ited more infiltration of myeloid-derived suppressor cells(MDSCs)and less infiltration of CD8? T cells.The synthesized Alpelisib-loaded pH-re-sponsive polymer micelles had an average size of approximately 127 nm.Treatment with Alpelisib and Alpelisib@MSPM reduced tumor growth in mice with PIK3CA-mutated Luminal breast cancer.Notably,the proportion of MDSCs decreased,whereas CD8? T cell infiltration in-creased significantly,with the more pronounced effect observed in the Alpelisib@MSPM treatment group.Conclusions:PIK3CA mutations drive the formation of a tumor immunosuppressive microenvironment in Luminal breast cancer.Targeted Alpelisib delivery via pH-respons-ive polymer micelles significantly enhances therapeutic efficacy in PIK3CA-mutated breast cancer.

Objective:To investigate the effect of PIK3CA mutations on the tumor immune microenvironment in Luminal breast cancer and evaluate the potential of Alpelisib-loaded pH-responsive polymer micelles in modulating the tumor immune microenvironment.Methods:PIK3CA mutations in breast cancer were analyzed using bioinformatics tools.A mouse xenograft model of Luminal breast cancer harboring a PIK3CA mutation was established,and alterations in the tumor immune microenvironment were examined using mass cytometry(CyTOF).During the period from August 2004 to December 2008 in Tianjin Medical University Cancer Hospital,tissue biopsies of 62 Luminal breast cancer patients in the BRCA cohort were collected Study the relationship between PIK3CA mutations and tumor immune microenvironment at the organizational level.Alpelisib-loaded polymer micelles(Alpelisib@MSPM)were synthesized,characterized,and evaluated for thera-peutic efficacy in Luminal breast cancer with PIK3CA mutations.Results:PIK3CA is one of the most frequently mutated genes in breast can-cer,with the highest prevalence in Luminal subtypes.CyTOF analysis demonstrated that PIK3CA mutations contribute to a tumor immun-osuppressive microenvironment in xenografts.Multiplex fluorescence immunohistochemistry revealed that PIK3CA-mutated tumors exhib-ited more infiltration of myeloid-derived suppressor cells(MDSCs)and less infiltration of CD8? T cells.The synthesized Alpelisib-loaded pH-re-sponsive polymer micelles had an average size of approximately 127 nm.Treatment with Alpelisib and Alpelisib@MSPM reduced tumor growth in mice with PIK3CA-mutated Luminal breast cancer.Notably,the proportion of MDSCs decreased,whereas CD8? T cell infiltration in-creased significantly,with the more pronounced effect observed in the Alpelisib@MSPM treatment group.Conclusions:PIK3CA mutations drive the formation of a tumor immunosuppressive microenvironment in Luminal breast cancer.Targeted Alpelisib delivery via pH-respons-ive polymer micelles significantly enhances therapeutic efficacy in PIK3CA-mutated breast cancer.

Colorectal cancer is currently one of the most common malignant tumors in the world,and its incidence and mortality rates have gradually increased in recent years.As insidious symptoms characterize early colorectal cancer,most of the patients have already developed into late or advanced stages in the primary survey.For stage Ⅳ metastatic colorectal cancer(mCRC),surgery supplemented with chemotherapy or radiotherapy for mCRC patients has a low 5-year survival rate.With the development of immunology in recent years,PD-1/PD-L1 inhibitors have made breakthroughs in treating malignant tumors.They also have improved the therapeutic efficacy of some mCRC patients,especially those with microsatellite instability-high/mismatch repair deficient.The guidelines recommend this approach.However,patients with microsatellite stable/mismatch repair proficiency,which accounts for more than 90%,are poorly treated with PD-1/PD-L1 inhibitors.Fortunately,there are several clinical studies that reported that some of this type of mCRC can gain some benefit.In this review,we examined the anti-tumor mechanism of PD-1/PD-L1 inhibitors and the latest progress of PD-1/PD-L1 inhibitor's clinical application in patients of mCRC with different genotypes.We discussed the prospect of PD-1/PD-L1 inhibitor combination therapy to provide a reference to the benefit of this type of patients and provide information for optimizing the dosing regimen of PD-1/PD-L1 inhibitors in the treatment of mCRC.