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Tumor‐infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells have demonstrated remarkable success in the treatment of relapsed/refractory melanoma and hematological malignancies, respectively. These treatments have marked a pivotal shift in cancer management. However, as “living drugs,” their effectiveness is dependent on their ability to proliferate and persist in patients. Recent studies indicate that the mechanisms regulating these crucial functions, as well as the T cell's differentiation state, are conditioned by metabolic shifts and the distinct utilization of metabolic pathways. These metabolic shifts, conditioned by nutrient availability as well as cell surface expression of metabolite transporters, are coupled to signaling pathways and the epigenetic landscape of the cell, modulating transcriptional, translational, and post‐translational profiles. In this review, we discuss the processes underlying the metabolic remodeling of activated T cells, the impact of a tumor metabolic environment on T cell function, and potential metabolic‐based strategies to enhance T cell immunotherapy. T cells engineered to express chimeric antigen receptors (CAR) are dependent on the transport and utilization of nutrients from the extracellular space, fueling their anti‐tumor activity. Nonetheless, the tumor microenvironment is characterized by a dearth of several key nutrients and alterations in metabolic scavenging systems. It is therefore critical to equip CAR T cells to optimally function in these unique environments.

Gas‐based therapy has emerged as a new green therapy strategy for anti‐tumor treatment. However, the therapeutic efficacy is still restricted by the deep tissue controlled release, poor lymphocytic infiltration, and inherent immunosuppressive tumor microenvironment (TME). Herein, a new type of nanovaccine is designed by integrating low dose soft X‐ray‐triggered CO releasing lanthanide scintillator nanoparticles (ScNPs: NaLuF4:Gd,Tb@NaLuF4) with photo‐responsive CO releasing moiety (PhotoCORM) for synergistic CO gas/immuno‐therapy of tumors. The designed nanovaccine presents significantly boosted radioluminescence and enables deep tissue CO generation at unprecedented tissue depths of 5 cm under soft X‐ray irradiation. Intriguingly, CO as a superior immunogenic cell death (ICD) inducer further reverses the deep tissue immunosuppressive TME and concurrently activates adaptive anti‐tumor immunity through efficient reactive oxygen species (ROS) generation. More importantly, the designed nanovaccine presents efficient growth inhibition of both local and distant tumors via a soft X‐ray activated systemic anti‐tumor immunoresponse. This work provides a new strategy of designing anti‐tumor nanovaccines for synergistic deep tissue gas‐therapy and remote soft X‐ray photoactivation of the immune response. A novel soft X‐ray remotely stimulated lanthanide scintillator‐based CO releasing system is designed. The nanovaccine presents efficient CO generation ability, which can further realize deep tissue gas therapy, activate a systemic anti‐tumor immune‐response, and reverse an immunosuppressive tumor microenvironment. The findings demonstrate a new strategy of designing anti‐tumor nanovaccines for soft X‐ray triggered deep tissue gas therapy and immune response.

Immune checkpoint inhibitor (ICI) therapy is a promising anti‐tumor therapeutic strategy; however, its efficacy in solid tumors is limited. Chromosome missegregation is common in various solid tumors; however, its role in tumor progression remains poorly understood, and its correlation with ICI is yet to be explored. Here, it is found that increased chromosome missegregation promotes tumor immune microenvironment, and eventually immunotherapeutic efficacy, by triggering pyroptosis. yin yang 2 (YY2) is identified as a mitotic checkpoint regulator, which promotes chromosome missegregation by upregulating BUB1B transcription. Increased chromosome missegregation promoted the formation of micronuclei and release of double‐stranded DNA (dsDNA) into the cytosol, triggering an AIM2‐mediated cytosolic dsDNA response. The subsequent pyroptosis strengthened the tumor immune microenvironment, thereby enhancing immunoinfiltration and cytotoxicity of CD8+ T cells, while preventing their exhaustion. Finally, through in vitro and in vivo experiments, it is demonstrated that combining YY2 overexpression‐induced chromosome missegregation/cytosolic dsDNA response and PD‐1 inhibitor significantly enhanced the efficacy of ICI immunotherapy in microsatellite instable and microsatellite stable colorectal cancer cells. Together, these findings provide new insights on the role of chromosome missegregation in triggering cytosolic dsDNA response‐mediated pyroptosis and modulating the tumor immune microenvironment, suggesting a novel strategy for improving ICI therapeutic efficacy in colorectal cancer. Immune system disorders and chromosome missegregation are two of the major hallmarks of tumor. The relationship between tumor immune and chromosome missegregation is still unclear. This study reveals that YY2 high expression‐mediated chromosome missegregation/micronuclei formation triggers pyroptosis and CTL activation by activating AIM2/caspase‐1/GSDMD cytosolic dsDNA response, and YY2/anti‐PD‐L1 combinatorial anti‐tumor therapeutic strategy.

Although metal peroxides are extensively employed in tumor therapy, novel synergistic tumor treatment approaches based on the combination of multiple types of metal peroxides are still lacking and warrant further exploration. To overcome this challenge, hyaluronic acid (HA)‐modified bimetallic peroxide nanocomposites (MgO2‐CuO2@HA NCs) are developed by combining magnesium peroxide (MgO2) nanosheets and short‐grained copper peroxide (CuO2) nanodots. By modifying HA to enhance tumor targeting and stability, MgO2‐CuO2@HA NCs leverage pH‐dependent decomposition to release Mg2+, H2O2, and Cu2+ under acidic conditions, thereby initiating Fenton‐like reactions for the generation of hydroxyl radicals (•OH), while simultaneously depleting glutathione to generate Cu+. This process induces cuproptosis through the Cu+‐mediated oligoaggregation of dihydrolipoamide S‐acetyltransferase. Additionally, enhanced •OH activates pyroptosis via the caspase‐1/gasdermin D pathway. Cuproptosis and pyroptosis can induce immunogenic cell death, thereby triggering the anti‐tumor immune responses. Notably, released Mg2+ can enhance the activation of CD8+ T cells by promoting the conformational activation of leukocyte function‐associated antigen 1. Therefore, this study establishes a novel paradigm for synergistic anti‐tumor immunotherapy based on bimetallic peroxide nanocomposites, offering promising prospects for clinical immunotherapy. Hyaluronic acid‐modified bimetallic peroxide nanocomposites (MgO2‐CuO2@HA) are designed for synergistic tumor therapy. The nanocomposites release Mg2+, H2O2, and Cu2+ in tumor cells, induce cuproptosis via Cu+‐mediated protein aggregation, and activate pyroptosis through caspase‐1/gasdermin D pathways for inducing immunogenic cell death, collectively promote the activation of CD8+ T cells by released Mg2+ for cancer immunotherapy with minimal systemic toxicity.

PD‐1 negatively regulates CD8 + cytotoxic T lymphocytes (CTL) cytotoxicity and anti‐tumor immunity. However, it is not fully understood how PD‐1 expression on CD8 + CTL is regulated during anti‐tumor immunotherapy. In this study, we have identified that the ADAP‐SKAP55 signaling module reduced CD8 + CTL cytotoxicity and enhanced PD‐1 expression in a Fyn‐, Ca 2+ ‐, and NFATc1‐dependent manner. In DC vaccine‐based tumor prevention and therapeutic models, knockout of SKAP55 or ADAP showed a heightened protection from tumor formation or metastases in mice and reduced PD‐1 expression in CD8 + effector cells. Interestingly, CTLA‐4 levels and the percentages of tumor infiltrating CD4 + Foxp3 + Tregs remained unchanged. Furthermore, adoptive transfer of SKAP55‐deficient or ADAP‐deficient CD8 + CTLs significantly blocked tumor growth and increased anti‐tumor immunity. Pretreatment of wild‐type CD8 + CTLs with the NFATc1 inhibitor CsA could also downregulate PD‐1 expression and enhance anti‐tumor therapeutic efficacy. Together, we propose that targeting the unrecognized ADAP‐SKAP55‐NFATc1‐PD‐1 pathway might increase efficacy of anti‐tumor immunotherapy. Synopsis ADAP and SKAP55 can enhance PD‐1 expression via the transcription factor NFATc1 in CD8 + CTLs. Targeting this pathway in CTLs enhances cytotoxic responses against tumor cells in vitro and in vivo . ADAP and SKAP55 regulate PD‐1 expression in a Fyn‐, Ca 2+ ‐ and NFATc1‐dependent manner. Deficiency of SKAP55 or ADAP enhances CD8 + CTL cytotoxicity and reduces PD‐1 expression. SKAP55‐ or ADAP‐deficient mice improve efficacy of a DC‐based vaccine for tumor prevention and therapy. Adoptive transfer of SKAP55‐ or ADAP‐deficient CD8 + CTLs significantly blocks tumor growth in wild‐type recipient mice. Graphical Abstract ADAP and SKAP55 can enhance PD‐1 expression via the transcription factor NFATc1 in CD8 + CTLs. Targeting this pathway in CTLs enhances cytotoxic responses against tumor cells in vitro and in vivo .

In the last decade several therapeutic antibodies have been Federal Drug Administration (FDA) and European Medicines Agency (EMEA) approved. Although their mechanisms of action in vivo is not fully elucidated, antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells is presumed to be a key effector function. A substantial role of ADCC has been demonstrated in vitro and in mouse tumor models. However, a direct in vivo effect of ADCC in tumor reactivity in humans remains to be shown. Several studies revealed a predictive value of FcγRIIIa-V158F polymorphism in monoclonal antibody treatment, indicating a potential effect of ADCC on outcome for certain indications. Furthermore, the use of therapeutic antibodies after allogeneic hematopoietic stem cell transplantation is an interesting option. Studying the role of the FcγRIIIa-V158F polymorphism and the influence of Killer-cell Immunoglobuline-like Receptor (KIR) receptor ligand incompatibility on ADCC in this approach may contribute to future transplantation strategies. Despite the success of approved second-generation antibodies in the treatment of several malignancies, efforts are made to further augment ADCC in vivo by antibody engineering. Here, we review currently used therapeutic antibodies for which ADCC has been suggested as effector function.

Chemokines play a critical role in regulating immune cell infiltration and their interactions with cancer cells in the tumor microenvironment (TME). Disrupted chemokine gradients influence immune cell recruitment and activation, as well as tumor cell proliferation, metastasis, and angiogenesis. By modulating these processes, chemokines shape the immune landscape of the tumor microenvironment, driving either immunosuppressive or immunostimulatory responses with corresponding pro- or antitumor effects. Dysregulated expression of chemokines and their receptors is strongly associated with tumor initiation, progression, and clinical outcomes. As a result, the chemokine receptor axis has gained prominence as a therapeutic target in cancer immunotherapy. This review explores chemokine expression profiles across various tumor types and their receptor-mediated interactions with immune cells. It also summarizes current strategies to therapeutically target chemokine signaling, both as standalone interventions and in combination with other treatment modalities.

Autophagy is a genetically well-controlled cellular process that is tightly controlled by a set of core genes, including the family of autophagy-related genes (ATG). Autophagy is a “double-edged sword” in tumors. It can promote or suppress tumor development, which depends on the cell and tissue types and the stages of tumor. At present, tumor immunotherapy is a promising treatment strategy against tumors. Recent studies have shown that autophagy significantly controls immune responses by modulating the functions of immune cells and the production of cytokines. Conversely, some cytokines and immune cells have a great effect on the function of autophagy. Therapies aiming at autophagy to enhance the immune responses and anti-tumor effects of immunotherapy have become the prospective strategy, with enhanced antigen presentation and higher sensitivity to CTLs. However, the induction of autophagy may also benefit tumor cells escape from immune surveillance and result in intrinsic resistance against anti-tumor immunotherapy. Increasing studies have proven the optimal use of either ATG inducers or inhibitors can restrain tumor growth and progression by enhancing anti-tumor immune responses and overcoming the anti-tumor immune resistance in combination with several immunotherapeutic strategies, indicating that induction or inhibition of autophagy might show us a prospective therapeutic strategy when combined with immunotherapy. In this article, the possible mechanisms of autophagy regulating immune system, and the potential applications of autophagy in tumor immunotherapy will be discussed.

In many hematologic malignancies, the adoptive transfer of chimeric antigen receptor (CAR) T cells has demonstrated notable success; nevertheless, further improvements are necessary to optimize treatment efficacy. Current CAR-T therapies are particularly discouraging for solid tumor treatment. The immunosuppressive microenvironment of tumors affects CAR-T cells, limiting the treatment’s effectiveness and safety. Therefore, enhancing CAR-T cell infiltration capacity and resolving the immunosuppressive responses within the tumor microenvironment could boost the anti-tumor effect. Specific strategies include structurally altering CAR-T cells combined with targeted therapy, radiotherapy, or chemotherapy. Overall, monitoring the tumor microenvironment and the status of CAR-T cells is beneficial in further investigating the viability of such strategies and advancing CAR-T cell therapy.

Macrophages phagocytize pathogens to initiate innate immunity and products from the tumor microenvironment (TME) to mediate tumor immunity. The loss of tumor-associated macrophage (TAM)-mediated immune responses results in immune suppression. To reverse this immune disorder, the regulatory mechanism of TAMs in the TME needs to be clarified. Immune molecules (cytokines and chemokines) from TAMs and the TME have been widely accepted as mutual mediators of signal transduction in the past few decades. Recently, researchers have tried to seek the intrinsic mechanism of TAM phenotypic and functional changes through metabolic connections. Numerous metabolites derived from the TME have been identified that induce the cell-cell crosstalk with TAMs. The bulk tumor cells, immune cells, and stromal cells produce metabolites in the TME that are involved in the metabolic regulation of TAMs. Meanwhile, some products from TAMs regulate the biological functions of the tumor as well. Here, we review the recent reports demonstrating the metabolic regulation between TME and TAMs.