In recent years, immunotherapy has become an excellent option for cancer patients, but most patients still face problems such as low response or drug resistance. Therefore, researchers conducted extensive studies on the reasons for the poor efficacy of immunotherapy. Eventually, it was found that the regulatory effect of abnormal expression of oncogenes and tumor suppressor genes on the tumor immune microenvironment is one of the important factors leading to the failure of immunotherapy to achieve the expected efficacy. It is well known that cancer is a kind of disease caused by the interaction between environmental and genetic factors, and the occurrence of cancer is mainly related to genetic alteration. Physiologically, the balance between oncogenes and tumor suppressor genes is crucial for DNA replication and proliferation regulation. However, under certain conditions, such as viral infection, chemical carcinogens or radiation, these genes may be mutated and eventually induce cancer. In addition, the combination of different gene mutations can also lead to significant differences among patients. For example, certain gene mutations are associated with the metastasis of cancer cells, while some are associated with the resistance of cancer cells to the attack of immune cells. Therefore, exploring the effects of different genetic alterations on the tumor microenvironment can help us better solve the problems in the process of clinical treatment and provide a theoretical basis for designing gene-targeted and personalized therapies. This review mainly summarizes the effects of common oncogenes and tumor suppressor gene mutations on immunosuppressive cells, anti-tumor immune effector cells and tumor-associated fibroblasts in the tumor microenvironment. Firstly, when the oncogene KRAS, cMyc and EGFR are abnormally activated, cancer cell will secrete various cytokines and chemokines, thereby recruiting various immunosuppressive cells to the TME and causing exhaustion of CD8⁺ T and NK cells. It can also reprogram CAFs and eventually promote the development of cancer. Furthermore, similar phenomena occur after the inactivation of tumor suppressor genes. For example, cancer cells with inactivated PTEN genes will secrete large amounts of IL-33 and LOX to recruit macrophages and induce TAMs. Cancer cells can secrete a variety of microRNAs into the tumor microenvironment after p53 dysregulation. These mircoRNAs can reprogram CAFs and lead to epithelial-mesenchymal transition. Finally, we summarize the reversing effects of therapeutic interventions targeting mutant oncogenes or tumor suppressor genes (such as KRAS inhibitors, overexpression of p53 by mRNA, PI3Kβ inhibitors) on the immunosuppressive tumor microenvironment. Some of the results of their synergistic effects in combination with immunotherapy are also listed. Compared with monotherapy, the combination of either KRAS inhibitor or p53 mRNA nanomedicine with αPD-1 therapy resulted in more durable and potent anti-tumor effects. In summary, this review elucidates the regulatory and remodeling effects of genetic alterations in tumor cells on the tumor immune microenvironment, and analyzes the great potential of gene alteration intervention combined with immunotherapy. We hope it can provide theoretical basis and development strategy for precise cancer immunotherapy.