There is a complex mechanism of interaction between tumor metabolism and immune regulation. The metabolic pathways and metabolites of tumor cells can directly or indirectly affect the function of immune cells and immune regulation, thus having an impact on the immunotherapy of tumors (28, 32–34).

The metabolic pathways of tumor cells can affect the biological activity of immune cells (35). Tumor cells often exhibit high levels of glycolysis and lactate production, leading to low pH and hypoxic conditions in the tumor microenvironment (36). These metabolic features affect immune cell function, such as altering immune cell growth, proliferation, antigen recognition and antigen presentation capabilities. In addition, the metabolic activity of tumor cells leads to the accumulation of some metabolites, such as lactate, adenosine and pyruvate, which have an immunosuppressive effect on immune cells and thus attenuate the immune response (37).

Metabolites of tumor cells can modulate the immune response by altering the signaling pathways of immune cells (35, 38). For example, metabolites such as lactate and adenylate can inhibit immune cell function by binding to the corresponding receptors on immune cells (39, 40). Adenosine and adenosine receptors may play an important immunosuppressive role in the tumor microenvironment, affecting immune cell proliferation, differentiation, antigen recognition and antigen presentation. In addition, some metabolites such as pyruvate and ketone bodies can also modulate the immune response by affecting the metabolic pathways and signaling pathways of immune cells (41).

The metabolic pathways and metabolites of tumor cells can also indirectly affect immune regulation by altering the composition and function of immune cells in the tumor microenvironment (11, 35, 42). For example, the metabolic profile of tumor cells may lead to alterations in the number and activity of immune cells in the tumor microenvironment, such that the functions of T cells, natural killer cells (NK cells), and dendritic cells can be suppressed, thus weakening the immune system’s ability to attack the tumor (43, 44). In addition, metabolites of tumor cells can also have an impact on immune tolerance of immune cells, leading to a decrease in the ability of immune cells to recognize and attack tumor cells.

Osteosarcoma tumor cells exhibit metabolic specificities such as increased glycolysis, altered mitochondrial function, and increased lactate production. These metabolic alterations produce an acidic, hypoxic, and nutrient-deprived microenvironment (45). The acidic microenvironment can inhibit the function of immune cells such as T cells and natural killer cells by altering the pH-sensitive signaling pathways that are necessary for their activation and proliferation (46). For example, the acidic microenvironment can inhibit the activity of enzymes involved in T cell receptor signaling, leading to impaired T cell activation and cytokine production (47). Additionally, the acidic microenvironment can promote the survival and proliferation of immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells, which can further inhibit the function of infiltrating immune cells (48). Hypoxia can promote the expression of immune checkpoint molecules such as PD-1 and CTLA-4, which can inhibit the function of infiltrating immune cells and promote immune escape of osteosarcoma cells (49). In a nutrient-poor microenvironment, immune cells may become metabolically stressed and unable to carry out their normal functions. This can result in decreased cytokine production, impaired cytotoxicity, and reduced activation and proliferation of immune cells (42). Additionally, nutrient deprivation can lead to the activation of stress response pathways, such as the unfolded protein response (UPR) and the integrated stress response (ISR), which can further impair immune cell function and promote the survival of osteosarcoma cells (50).

Immunosenescence is the phenomenon of gradual decline in the function of the human immune system with age, which is mainly manifested by a decrease in the body’s immune response to endogenous and exogenous antigens, a lack of responsiveness to new antigens, and a blunted response to the protective effects of vaccines and established immune memory, resulting in a decrease in the individual’s ability to defend against infectious diseases, anti-tumor capacity, and the ability to clear senescent cells with age (77–81). It is a physiological phenomenon, but may also accelerate the onset and progression of disease. As an epidemiological study of osteosarcoma shows that the second peak in osteosarcoma is over 65 years of age (82). The age of the patient is correlated with the survival, with the poorest survival among older patients (82, 83). Therefore, the exploration of the mechanism of age-related immune senescence may provide new ideas for the treatment of this population.

Immunosenescence is associated with a decrease in the number and function of immune cells (84–86). With aging, there is a gradual decrease in the number and activity of immune cells in the body, including T cells, B cells, natural killer cells, and other immune cells. This may lead to a weakened immune response of the body to pathogens and tumor cells, thus increasing the risk of infection and tumor development.

Alterations in immune cell function also play a role in immunosenescence (84, 85, 87). With aging, immune cell functions are affected, including antigen presentation, antibody production, and cytotoxic activity. For example, T cells in the elderly may exhibit reduced proliferation and activity and a diminished response to novel antigenic stimuli, resulting in diminished immune memory and a decreased antigen-specific immune response.

Immunosenescence is related to altered inflammatory status (88). With advancing age, the body may develop a chronic inflammatory state called “inflammatory aging”. This chronic inflammatory state leads to an excessive inflammatory response of immune cells in response to pathogens and tumor cells, thus affecting the function and regulation of immune cells.

Alterations in immune regulatory networks also have an impact on immunosenescence (89–91). The normal function of the immune system depends on complex immune regulatory networks, including the interactions between immune cells, the production and action of cytokines, and the signaling between immune cells and target cells. As we age, these immune regulatory networks may change, leading to abnormal immune responses and disruption of immune tolerance.

With aging, the immune microenvironment of osteosarcoma will exhibit some senescence characteristics, which will have an impact on the immune response and disease process of osteosarcoma (31, 77, 92). As the aging process of the body continues to progress, the number and function of immune cells in the body will decline, including T cells, B cells, natural killer cells, and other immune cells (84, 87, 93, 94). This will lead to a weakened immune response in patients with osteosarcoma, which will increase the escape and survival of tumor cells. The function of immune cells will also be affected, including antigen presentation, antibody production, and cytotoxic activity. T cells will show reduced proliferation and activity, and a diminished response to new antigenic stimuli, resulting in a decreased immune response. At the same time, the immune microenvironment in osteosarcoma can develop a chronic inflammatory state (88, 95, 96). This chronic inflammatory state leads to an excessive inflammatory response of immune cells in response to tumor cells, which affects the function and regulation of immune cells. In addition, chronic inflammation may also promote the survival and proliferation of tumor cells (97). The immune regulatory network in the immune microenvironment of osteosarcoma will also be altered, including the interaction between immune cells, the production and action of cytokines, and the signaling between immune cells and tumor cells (98). This will lead to abnormal immune response and disruption of immune tolerance, thus affecting the immune surveillance and anti-tumor immune response to tumor cells in patients with osteosarcoma

With aging of the immune microenvironment, tumor cells can escape from immune surveillance by various mechanisms, such as reduced antigen presentation and antigen expression, altered evasive expression of antigens, and reduced recognition and killing of tumor antigen-specific T cells, thereby shielding tumor cells from immune attack (85, 86, 93). Figure 3 briefly describes the process mechanism of cancer initiation, elimination, equilibrium and escape under the influence of immune cells in the immune microenvironment. Senescence of the immune microenvironment may also lead to disruption of immune tolerance mechanisms, enabling tumor cells to escape clearance in the immune system, thus promoting tumor cell survival and proliferation (99). Senescence of the immune microenvironment may also lead to an increase in immunosuppressive factors, such as an increase in anti-inflammatory cytokines and an increase in immunosuppressive cells, which may inhibit the activity and function of immune cells and affect the antitumor immune response (100). Aging may lead to a decrease in the memory function of immune cells, thus reducing the specific attack on osteosarcoma cells (101). Decreased immune memory may lead to a reduced ability of immune cells to re-attack osteosarcoma cells, thus affecting the effectiveness of immunotherapy (102).

The immune microenvironment of osteosarcoma exhibits features such as diminished immune cell numbers and functions, altered immune regulatory networks, and altered inflammatory status during aging, which affect the immune response and disease process in osteosarcoma (103). Several studies have shown that intervening in the senescence features of the immune microenvironment in osteosarcoma (104), may help to enhance the effectiveness of immune cell attack on osteosarcoma cells and thus improve the efficacy of immunotherapy (105–107). For example, some studies have shown that by inhibiting immunosuppressive pathways such as PD-1/PD-L1 and CTLA-4, the ability of immune cells to attack osteosarcoma cells can be restored, thereby improving the efficacy of immunotherapy (15, 16, 108–110).

Several compounds and drugs are used to counteract immunosenescence, the age-related decline in immune function. Some of the most common ones include: 1) Thymosin alpha 1 (Tα1): Tα1 is a peptide that has been shown to enhance T-cell function and modulate the immune response (111). It can improve the production and maturation of T cells, which decline with age, thus counteracting immunosenescence (112). 2) Interleukin-7 (IL-7): IL-7 is a cytokine that plays a crucial role in the development and maintenance of T cells (113). Recombinant IL-7 therapy has been shown to increase T cell numbers and improve immune function in aged individuals (114). 3) PD-1/PD-L1 inhibitors: These drugs, such as pembrolizumab and nivolumab, target the immune checkpoint proteins PD-1 and PD-L1 (115). These proteins are often upregulated in aged immune cells and contribute to immune senescence. By blocking the interaction between PD-1 and PD-L1, these inhibitors can enhance the immune system’s ability to recognize and attack pathogens and cancer cells. 4) CTLA-4 inhibitors: Ipilimumab is a monoclonal antibody that targets the immune checkpoint protein CTLA-4 (116). CTLA-4 is expressed on the surface of T cells and acts as a negative regulator of T cell activation (117). By blocking CTLA-4, ipilimumab can enhance T cell activation and promote a more robust immune response (118). 5) Senolytics: These compounds selectively target and eliminate senescent cells, which accumulate with age and contribute to immunosenescence (119). Examples of senolytics include dasatinib, quercetin, and navitoclax. By removing senescent cells, senolytics can reduce inflammation and improve immune function (120). 6) Rapamycin (sirolimus): Rapamycin is an immunosuppressive drug that specifically targets the mTOR pathway (121). By inhibiting the mTOR pathway, rapamycin can suppress age-related changes in immune cells and improve immune function, although its use as an anti-immunosenescence agent should be approached with caution due to its immunosuppressive properties (122). These drugs and compounds have different mechanisms of action, but they all aim to improve immune function and counteract immunosenescence.

Several compounds and drugs can be used for metabolic regulation of the immune microenvironment of tumor cells. Some of the most common ones include: 1) Metformin: Metformin is a widely used drug for treating type 2 diabetes. It has been shown to have anti-cancer properties by modulating the tumor microenvironment (123). Metformin activates AMP-activated protein kinase (AMPK), which regulates cellular metabolism and inhibits the mammalian target of rapamycin (mTOR) pathway (124). This can lead to reduced nutrient availability for tumor cells and improved immune cell function within the tumor microenvironment (125). 2) 2-Deoxy-D-glucose (2-DG): 2-DG is a glucose analog that inhibits glycolysis, a key metabolic pathway used by cancer cells for energy production (126). By inhibiting glycolysis, 2-DG can alter the metabolic landscape of the tumor microenvironment, making it less favorable for tumor growth and more supportive of immune cell infiltration and function (127). 3) Dichloroacetate (DCA): DCA is a small molecule that targets pyruvate dehydrogenase kinase (PDK), an enzyme involved in the regulation of glucose metabolism. By inhibiting PDK, DCA can shift cancer cell metabolism from glycolysis to mitochondrial oxidative phosphorylation, reducing lactate production and acidification of the tumor microenvironment (128). This can improve immune cell function and enhance anti-tumor immunity. 4) Indoleamine 2,3-dioxygenase (IDO) inhibitors: IDO is an enzyme that degrades the essential amino acid tryptophan, leading to immunosuppression within the tumor microenvironment (129). IDO inhibitors, such as epacadostat and indoximod, can restore tryptophan levels and improve immune cell function, promoting anti-tumor immunity (130). 5) Adenosine receptor antagonists: Adenosine is an immunosuppressive molecule that accumulates in the tumor microenvironment (131). Adenosine receptor antagonists, such as CPI-444 and AZD4635, can block the interaction between adenosine and its receptors on immune cells, enhancing immune cell activation and anti-tumor responses (132). 6) CD73 inhibitors: CD73 is an enzyme that generates adenosine in the tumor microenvironment, contributing to immunosuppression (133). CD73 inhibitors, such as oleclumab and NZV930, can block adenosine production and improve immune cell function, promoting anti-tumor immunity (134). These compounds and drugs target different aspects of tumor cell metabolism and the immune microenvironment, aiming to improve immune cell function and promote anti-tumor responses. It is important to note that some of these compounds are still under investigation, and their long-term safety and efficacy have not been fully established.

As a highly aggressive tumor, traditional treatments for osteosarcoma include surgery, radiotherapy and chemotherapy, but their efficacy remains limited in advanced or recurrent osteosarcoma (135–137). Therefore, in recent years, immunotherapy has attracted much attention as a new treatment strategy (1, 105). Immunotherapy uses the body’s immune system to attack tumor cells by enhancing the ability of immune cells to recognize and attack tumors. In osteosarcoma, immunotherapy mainly includes immune checkpoint inhibitors, tumor vaccines, cellular immunotherapy and gene editing immunotherapy.

Currently, immune checkpoint inhibitors have made some progress in the clinical application of osteosarcoma as the most used immunotherapeutic agents (1, 72, 107, 138, 139). Immune checkpoint inhibitors, such as PD-1, B7-H3 and CTLA-4 inhibitors, enhance the ability to attack tumors by relieving the suppression of immune cells and activating the body’s immune response (104, 108, 110, 140, 141). Several clinical trials have shown that immune checkpoint inhibitors have achieved some clinical efficacy in a subset of patients with osteosarcoma (108, 142–147). However, overall, the sensitivity of osteosarcoma to immune checkpoint inhibitors is not high, and further validation of the therapeutic effect is needed (140, 147, 148).

Tumor vaccines have also shown potential as an individualized immunotherapeutic strategy in osteosarcoma (149, 150). Tumor vaccines can stimulate a tumor-specific immune response by directing the body’s immune system to recognize and attack tumor cells. Tumor vaccines are mainly classified as autologous cancer and immune cell-based vaccines and non-cell-based vaccines (149, 151, 152). Among these types, immune cell-based vaccines make full use of innate immune cells to activate effector T lymphocytes (153, 154). However, the feasibility of regulating migration and activation is a major issue, as these processes are regulated by immunosuppressive substances in the tumor microenvironment as well as by the quantity and quality of the patient’s immune effector cells (149).

Cellular immunotherapy, such as CAR-T cell therapy, has achieved remarkable efficacy in some tumors, especially hematologic tumors, but its application in solid tumor such as osteosarcoma remains challenging ( Figure 4 ) (155–161). The complex immune microenvironment of osteosarcoma and the high heterogeneity of tumor cells have limited the application of cellular immunotherapy in osteosarcoma (158, 162). In addition, there are certain resistance mechanisms of osteosarcoma cells to CAR-T cell attack, including T cell suppression, cytokine tolerance, and immune escape from the tumor microenvironment (158, 163).

Gene editing immunotherapy is an emerging immunotherapeutic strategy that includes technologies such as CRISPR-Cas9 that can target specific genes in tumor cells for editing, thereby enhancing the ability of immune cells to attack tumors (161, 164–166). Although gene editing immunotherapy in osteosarcoma is still in its early stages of research, it has made some breakthroughs in treating other types of tumors, offering new hope for immunotherapy of osteosarcoma (166–168).