Background: Colorectal liver metastases (CRLM) are known to respond poorly to immune checkpoint inhibitors (ICI), due to their immune-suppressive tumor microenvironment (TME). This study aimed to assess the clinical outcome of atezolizumab, bevacizumab and FOLFOX (ABFOLFOX) for patients (pts) with unresectable CRLM and to analyze the transcriptomics of the serial tumor samples from CRLM. Methods: This study was an open-label, single-arm pilot study. Pts with untreated CRLM, not amenable to surgery or other local treatment modalities (LTM), were eligible for this study. The presence of extrahepatic metastases (mets) treatable with LTM were allowed. All pts underwent liver biopsy at baseline(T0), and then received a single dose of atezolizumab 1200mg (cycle 0: C0), and then underwent the second liver biopsy on day 15 of C0 (T1). ABFOLFOX were given from day 21 after C0 (C1). ABFOLFOX was repeated every 2 weeks up to cycle 12. Pts could undergo hepatic resection, as determined through multi-disciplinary discussion, at any time point when CLRM became resectable. If CLRM remains unresectable until C12, the pt underwent liver biopsy (T2). Transcriptome sequencing on the tissues obtained sequentially were performed. Immune cell profiling and pathway analyses were performed using the transcriptome data. Results: 20 pts were enrolled between May 2018 and March 2021, and 17 (85%) completed 12 cycles of ABFOLFOX. Pts and disease characteristics were as follows: median age 56.5 years, primary tumor location right/left 1/19, unilobar/bilobar involvement of liver 3/17, ≥4 CLRM deposits in 17 (85%), 4 with extrahepatic mets, mismatch repair proficient/unknown 18/2, RAS or BRAF mutant in 7 (35%). 13 (65%) were treated with LTM for CRLM; 11 underwent hepatic resection and 2 underwent stereotactic radiotherapy. Overall response rate was 80% (16/20), and progression-free survival (PFS) was 22.7 months and overall survival at 24 months was 88%. Among response-evaluable pts (n=19), 7 (37%) remains disease-free beyond 24 months (good responders), including 2 with complete pathologic responses in CRLM and 1 durable responder without LTM, compared with other 12 (63%, average responders) in whom the median PFS was 11.1 months. Transcriptomic analysis showed serial increment by time (T0-T1-T2) in expression of immune related genes and total immune score including cytotoxic T cell was more notable in good responders than in average responders, while the baseline (T0) immune cell scores were similar between the two groups. Conclusions: Neoadjuvant ABFOLFOX induced durable responses more than 24 months with or without LTM in 37% of pts with unresectable CRLM. Serial immune cell expansion was identified in CRLM of good responders, suggesting immune monitoring can be useful in identifying pts who may derive durable benefits from ICIs in CRLM. Clinical trial information: 03698461.