Tumor-intrinsic ENO1 inhibition promotes antitumor immune response and facilitates the efficacy of anti-PD-L1 immunotherapy in bladder cancer
Abstract Immunotherapy has revolutionized cancer treatment, yet understanding immunotherapy resistance mechanisms remains challenging. Here, a CRISPR cas9 screening in vivo and an RNA-sequencing for clinical immunotherapy resistance BC samples identified enolase 1 (ENO1) as a potent regulator of ant...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-07-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-025-03464-x |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | Abstract Immunotherapy has revolutionized cancer treatment, yet understanding immunotherapy resistance mechanisms remains challenging. Here, a CRISPR cas9 screening in vivo and an RNA-sequencing for clinical immunotherapy resistance BC samples identified enolase 1 (ENO1) as a potent regulator of anti-PD-L1 treatment efficacy. Investigation of clinical BC samples demonstrated a correlation between ENO1 overexpression and immune evasion in BC, evidenced by reduced CD8+ T cell infiltration and resistance to anti-PD-L1 therapy. Increased CD8+ T cell infiltration and function were indicative of antitumor immunity, which was elicited by ENO1 knockdown, which also suppressed carcinogenesis. Single-cell RNA sequencing demonstrated that wild-type (WT) and ENO1 knockout (KO) tumors have different immune cell compositions with the latter preferring an immunostimulatory microenvironment. Mechanistically, ENO1 regulated CD8+ T cell function and tumor-associated macrophage (TAM) polarization via the SPP1-ITGA4/ITGB1 pathway in the TME. Importantly, genetic and pharmacological inhibition of ENO1 sensitizes tumors to anti-tumor immunity and synergizes with anti-PD-L1 therapy. The results highlight tumor-intrinsic ENO1 as a critical regulator of tumor immune evasion in BC. Targeting ENO1 enhance the efficacy of immune checkpoint blockade therapy by promoting antitumor immunity. |
|---|---|
| ISSN: | 1756-9966 |