Liver metastasis, the leading cause of colorectal cancer mortality, exhibits a highly heterogeneous and suppressive immune microenvironment. Here, we sequenced 97 matched samples by using single-cell RNA sequencing and spatial transcriptomics. Strikingly, the metastatic microenvironment underwent remarkable spatial reprogramming of immunosuppressive cells such as MRC1+ CCL18+ M2-like macrophages. We further developed scMetabolism, a computational pipeline for quantifying single-cell metabolism, and observed that those macrophages harbored enhanced metabolic activity. Interestingly, neoadjuvant chemotherapy could block this status and restore the antitumor immune balance in responsive patients, whereas the nonresponsive patients deteriorated into a more suppressive one. Our work described the immune evolution of metastasis and uncovered the black box of how tumors respond to neoadjuvant chemotherapy. Significance: We present a single-cell and spatial atlas of colorectal liver metastasis and found the highly metabolically activated MRC1+ CCL18+ M2-like macrophages in metastatic sites. Efficient neoadjuvant chemotherapy can slow down such metabolic activation, raising the possibility to target metabolism pathways in metastasis.

Purpose: To investigate the prognostic value of tumor-infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs), in hepatocellular carcinoma (HCC) patients after resection. Patients and Methods: CD3⁺, CD4⁺, CD8⁺, Foxp3-positive, and granzyme B-positive TILs were assessed by immunohistochemistry in tissue microarrays containing HCC from 302 patients. Prognostic effects of low- or high-density TIL subsets were evaluated by Cox regression and Kaplan-Meier analysis using median values as cutoff. Results: CD3⁺, CD4⁺, CD8⁺ TILs were associated with neither overall survival (OS) nor disease-free survival (DFS). The presence of low intratumoral Tregs in combination with high intratumoral activated CD8⁺ cytotoxic cells (CTLs), a balance toward CTLs, was an independent prognostic factor for both improved DFS (P = .001) and OS (P < .0001). Five-year OS and DFS rates were only 24.1% and 19.8% for the group with intratumoral high Tregs and low activated CTLs, compared with 64.0% and 59.4% for the group with intratumoral low Tregs and high activated CTLs, respectively. Either intratumoral Tregs alone (P = .001) or intratumoral activated CTLs (P = .001) alone is also an independent predictor for OS. In addition, high Tregs density was associated with both absence of tumor encapsulation (P = .032) and presence of tumor vascular invasion (P = .031). Conclusion: Tregs are associated with HCC invasiveness, and intratumoral balance of regulatory and cytotoxic T cells is a promising independent predictor for recurrence and survival in HCC. A combination of depletion of Tregs and concomitant stimulation of effector T cells may be an effective immunotherapy to reduce recurrence and prolong survival after surgery.

Importance: Approximately half of newly-diagnosed hepatocellular carcinoma (HCC) cases in the world occur in China, with hepatitis B virus (HBV) infection being the predominant risk factor. Recently, the guidelines for the management of Chinese HCC patients were updated. Objective: The past decade has witnessed a great improvement in the management of hepatocellular carcinoma (HCC). This study reviews the recommendations in the 2019 Chinese guidelines and makes comparison with the practices from the Western world. Evidence Review: The updated recommendations on the surveillance, diagnosis, and treatment algorithm of HCC in the 2019 Chinese guidelines were summarized, and comparisons among the updated Chinese guidelines, the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) guidelines were made. Findings: Besides imaging and pathological diagnoses, novel biomarkers like the seven-micro-RNA panel are advocated for early diagnoses and therapeutic efficacy evaluation in the updated Chinese guidelines. The China liver cancer (CNLC) staging system, proposed in the 2017 guidelines, continues to be the standard model for patient classification, with subsequent modifications and updates being made in treatment allocations. Compared to the Barcelona Clinic Liver Cancer (BCLC) system, the CNLC staging system employs resection, transplantation, and transarterial chemoembolization (TACE) for more progressed HCC. TACE in combination with other regional therapies like ablation or with systemic therapies like sorafenib are also encouraged in select patients in China. The systemic treatments for HCC have evolved considerably since lenvatinib, regorafenib, carbozantinib, ramucirumab and immune checkpoint inhibitors (ICIs)were first prescribed as first-line or second-line agents. Conclusions and Relevances: Novel biomarkers, imaging and operative techniques are recommended in the updated Chinese guideline. More aggressive treatment modalities are suggested for more progressed HBV-related HCC in China.