Tumor Escape

Immune evasion represents a significant challenge in oncology. It allows tumors to evade immune surveillance and destruction, thereby complicating therapeutic interventions and contributing to suboptimal patient outcomes. This review addresses the critical need to understand how cancers evade immune surveillance. It aims to provide a comprehensive overview of strategies of tumors to escape immune detection by examining tumor-induced immune suppression, immune checkpoint regulation, and genetic and epigenetic influences. Moreover, it explores the dynamic role of the tumor microenvironment (TME) in fostering immune resistance and highlights the impact of metabolic reprogramming on immune suppression. Additionally, this review focuses on how tumor heterogeneity influences immune evasion and discusses the limitations of current immunotherapies. The role of key signaling pathways, including programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), transforming growth factor-β (TGF-β), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) is analyzed to elucidate their contributions to immune escape. Emphasizing the complexities of immune evasion, this review underscores the importance of personalized approaches and the integration of multi-omics data to combat therapeutic resistance. Furthermore, it discusses novel and emerging therapeutic strategies, such as bispecific antibodies, oncolytic viruses, and nanotechnology-driven immunotherapies, showcasing innovative avenues in cancer treatment. The significance of this review lies in its potential to guide future research and innovations in immunotherapy, ultimately improving patient outcomes and advancing our understanding of cancer immunology.

Rationale: Tumor cells possess sophisticated strategies to circumvent immune detection, including the modulation of endogenous immune checkpoints, particularly those within the B7 family. Elucidating the mechanisms that govern the induction of B7 family molecules is crucial for the advancement of immunotherapy. Lysine lactylation (Kla), a newly identified epigenetic modification, is suggested may play a role in reshaping the tumor microenvironment and facilitating immune evasion. Methods: We analyzed the glycolysis pathway's enrichment in patients with immune-evading tumors and assessed the impact of lactate treatment on the antitumor immunity of CD8+ T cells in the tumor microenvironment. We interrupted glycolysis using lactate dehydrogenase A (LDHA) knockdown and sodium oxamate, and evaluated its effects on CD8+ T cell cytotoxicity. Additionally, we investigated the correlation between B7-H3 expression and the glycolysis pathway, and explored the molecular mechanisms underlying lactate-induced B7-H3 expression. Results: Our findings revealed that the glycolysis pathway was highly enriched in immune-evading tumors. Lactate treatment inhibited the antitumor immunity of CD8+ T cells, whereas interruption of glycolysis via LDHA knockdown or treatment with sodium oxamate augmented the cytotoxicity of CD8+ T cells, effectively counteracting tumor immune evasion. B7-H3 expression was found to be closely linked with the glycolysis pathway. Mechanistically, lactate-upregulated H3K18la directly bound to the B7-H3 promoter in conjunction with the transcription factor Creb1 and its co-activator Ep300, leading to increased B7-H3 expression and contributing to tumor progression by compromising the proportion and cytotoxicity of tumor-infiltrating CD8+ T cells. In mouse tumor bearing models, inhibiting glycolysis and B7-H3 expression suppressed tumor cell growth, activated tumor-infiltrating CD8+ T cells, and demonstrated potent anti-tumor efficacy. Furthermore, this approach enhanced the efficacy of anti-PD-1 treatment. Conclusions: This study uncovers a novel mechanism by which lactate modulates the immune microenvironment through the glycolysis pathway and B7-H3 expression, providing new avenues for lactate metabolism-targeted tumor immunotherapy.

BackgroundV-set and immunoglobulin domain containing 4 (VSIG4) is a B7-family-related protein almost exclusively expressed on macrophages. The difference in its expression mediates the dynamic transformation of the polarization state of macrophages, but the underlying mechanism is still unclear. We sought to reveal the correlation between VSIG4 and the polarization of tumour-associated macrophages (TAMs) and the immune escape of tumour cells in colorectal cancer (CRC).MethodsTHP-1 monocyte-derived macrophages expressing different levels of VSIG4 were used for in vitro investigations. In addition, the co-culture system was used to verify the effect of tumour cells on the expression of VSIG4 in macrophages, and the effect of VSIG4 expression level on tumour cells in turn. Subcutaneous xenograft models evaluated the tumour growth inhibition efficacy of VSIG4 blockade as monotherapy and combined with immune checkpoint inhibitors (ICIs).ResultsCRC cells secreted lactate to promote VSIG4 expression in macrophages. On the contrary, VSIG4 promoted macrophage M2 polarization and induced malignant progression of tumour cells by promoting M2 macrophage secretion of heparin-bound epidermal growth factor. In vivo experiments confirmed that knockdown VSIG4 inhibited tumour growth and improved the efficacy of ICIs therapy. Mechanistically, lactate secreted by CRC cells promoted its expression by influencing the epigenetic modification of VSIG4 in macrophages. In addition, VSIG4 enhanced the fatty acid oxidation (FAO) of macrophages and upregulated PPAR-γ expression by activating the JAK2/STAT3 pathway, which ultimately induced M2 polarization of macrophages. Downregulation of VSIG4 or blocking of FAO reversed the M2 polarization process of macrophages.ConclusionsOur findings provide a molecular basis for VSIG4 to influence TAMs polarization by regulating the reprogramming of FAO, suggesting that targeting VSIG4 in macrophages could enhance the ICIs efficacy and represent a new combination therapy strategy for immunotherapy of CRC.Key pointsColorectal cancer cells secrete lactate to upregulate VSIG4 in macrophages via the H3K18la-METTL14-m6A axis. VSIG4 promotes fatty acid oxidation of macrophages and drives its M2-type polarization. These VSIG4-expressing M2 macrophages promote tumour progression and an immunosuppressive microenvironment. Inhibition of VSIG4 expression can synergistically enhance the therapeutic effect of anti-PD-1 antibody.

Programmed death-ligand 1 (PD-L1) plays a critical role in tumor immune evasion, yet the mechanisms that regulate its expression, specifically the metabolic control of its stability and function, remain elusive. In this study, we demonstrate that lactate, a key metabolite in the tumor microenvironment, upregulates PD-L1 expression via lysine lactylation (Kla) of PD-L1 at residue K280 within its intracellular domain. This modification stabilizes PD-L1 by inhibiting E3 ligase HUWE1 binding, ubiquitination, and subsequent proteasomal degradation. We identified alanyl-tRNA synthetase 1 (AARS1) as the lactyltransferase that utilizes lactate as a lactyl-donor and is responsible for PD-L1 K280 lactylation. Functionally, PD-L1 lactylation promotes tumor immune evasion by impairing CD8 + T cell-mediated cytotoxicity and accelerates tumor growth in vivo. Furthermore, sodium lactate (NaLa) administration enhances the efficacy of anti-PD-L1 immunotherapy in preclinical models. Clinically, PD-L1 K280 lactylation correlates with advanced non-small cell lung cancer stages and poor patient survival, highlighting its potential as a diagnostic biomarker. Our findings unveil a novel lactate-PD-L1 regulatory axis and propose lactylation as a therapeutic target to augment the efficacy of the immune checkpoint blockade.