Abstract： Objective： To observe the clinical efficacy of Tuoli Xiaozheng Prescription combined with targeted therapy and immunotherapy in the treatment of intermediate-to-advanced primary liver cancer， and to explore its effects on tumor immune microenvironment-related indicators. Methods：A total of 70 patients with intermediate-to-advanced primary liver cancer admitted to Dongguan Traditional Chinese Medicine Hospital from March 2023 to December 2024 were enrolled. They were randomly divided into an observation group and a control group using the random number table method， with 35 cases in each group. The control group received Lenvatinib combined with Tislelizumab， while the observation group received additional oral administration of Tuoli Xiaozheng Prescription on this basis， with a continuous treatment course of 12 weeks. The two groups were compared in terms of objective response rate （ORR）， disease control rate （DCR）， changes in tumor microenvironment-related cytokines [interleukin （IL）-2， IL-4， IL-6， IL-10， interferon-gamma （IFN-γ）， tumor necrosis factor-alpha （TNF-α）]， liver fibrosis indicators [hyaluronic acid（ HA），laminin（ LN），typeⅣcollagen（ Ⅳ-C），procollagen type Ⅲ（PC-Ⅲ）]， liver function indicators [aspartate aminotransferase （AST），total bilirubin （TBil），alanine aminotransferase （ALT）， albumin（ ALB）]，traditional Chinese medicine syndrome scores，and Karnofsky Performance Status（ KPS） scores，as well as the incidence of adverse reactions. Results： The ORR of the observation group was 42.9% （15/35）， higher than the 34.3% （12/35） of the control group，and the DCR of both groups was 94.3% （33/35），with no statistically significant differences （P＞0.05）. After treatment，serum levels of IL-2 and IFN-γ in both groups increased compared with those before treatment （P＜0.05）， and the levels of IL-2 and IFN-γ in the observation group were higher than those in the control group （P＜0.05）；serum levels of IL-6，IL-10，and TNF-α in the observation group decreased compared with those before treatment （P＜0.05）， and were lower than those in the control group （P＜0.05）. After treatment， serum levels of HA， LN， Ⅳ -C， and PC- Ⅲ in both groups decreased compared with those before treatment（ P＜0.05），and the levels of these four liver fibrosis indicators in the observation group were lower than those in the control group （P＜0.05）. After treatment， serum ALT and AST levels in the observation group decreased compared with those before treatment （P＜0.05）， and the ALT level was lower than that in the control group （P＜ 0.05）. After treatment，serum AFP and CEA levels in both groups decreased compared with those before treatment （P＜ 0.05）. After treatment， traditional Chinese medicine syndrome scores in both groups decreased （P＜0.05） and KPS scores in both groups increased （P＜0.05） compared with those before treatment； the traditional Chinese medicine syndrome score in the observation group was lower （P＜0.05） and the KPS score in the observation group was higher （P＜0.05） than those in the control group. The incidence of adverse reactions in the observation group was 57.1% （20/35）， lower than the 80.0% （28/35） in the control group （P＜0.05）. Conclusion： Tuoli Xiaozheng Prescription combined with targeted therapy and immunotherapy in the treatment of intermediate-to-advanced primary liver cancer can effectively regulate the tumor immune microenvironment， alleviate liver fibrosis， improve liver function，alleviate clinical symptoms，enhance quality of life，and reduce treatment-related adverse reactions.