InVivoMAb anti-mouse PD-L1 (B7-H1)

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor that represents a significant therapeutic challenge because of its immunosuppressive tumor microenvironment (TME). GBM employs multiple sophisticated mechanisms for immune evasion, including proinflammatory cytokine secretion and immune cell effector function impairment. Due to these complex immune evasion strategies, immunotherapies are effective in only a minority of GBM patients. Herein, we identified P21-activated kinase 4 (PAK4) as a critical immunosuppressive gene that is highly expressed in GBM and actively promotes tumor progression. Mechanistically, PAK4 mediates transforming growth factor-beta 1 (TGF-β1) release from GBM cells, triggering PI3K/AKT/NF-κB signalling pathway activation in CD8 + T cells, which consequently upregulates phospholipase A2 group IVA (PLA2G4A) expression. PLA2G4A activation triggers phosphatidylcholine (PC) depletion in CD8 + T cells, damages mitochondrial and lysosomal functions, inducing subsequent mitophagic flux suppression, which culminates in the functional exhaustion of CD8 + T cells. Furthermore, PLA2G4A inhibitor treatment effectively reduces CD8 + T cell exhaustion while enhancing T cell cytotoxic capacity. Finally, combined PAK4 inhibitor and anti-PD-L1 therapy increases the CD8 + T cell cytotoxic function and suppresses tumor growth. Overall, our study results suggest that targeting PAK4 could be a potential strategy for GBM immunotherapy.

Patients with impaired tumour-specific major histocompatibility complex class I (tsMHC-Iimpaired) often fail to respond to immune checkpoint blockade (ICB), presenting a major clinical challenge. However, through our multicentre investigation, we observed that a subset of patients with tsMHC-Iimpaired remains responsive to ICB, a phenomenon that has not been fully explained. Here we identify a COTL1high natural killer (NK) subset that mediates ICB responsiveness in these patients. Mechanistically, PD-L1+ macrophages coexpress GITRL and engage GITR on COTL1high NK cells, whereas PD-L1 blockade relieves the PD-1-mediated inhibition of GITR signalling and promotes NK cell activation. Activated COTL1high NK cells enhance immunological synapse stability and IFN-γ production via a metabolic-H3K27ac-RBPJ axis, thereby upregulating tsMHC-I expression and reinforcing adaptive anti-tumour immunity. Notably, GITR activation significantly enhances the sensitivity to anti-PD-L1 therapy in tsMHC-Iimpaired models. Our findings identify COTL1high NK cells as key determinants of ICB responsiveness and highlight the GITRL-GITR axis as a promising therapeutic target for tsMHC-Iimpaired tumours.

Bone marrow adipocytes are known to have a critical role within the bone marrow niche. However, our understanding of bone marrow adipose tissue expansion with obesity and the role it plays in immune cell regulation and osteoclastogenesis is limited. Here, we showed the expansion of bone marrow adipocytes promoted osteoclast differentiation and subsequently led to obesity-related trabecular and cortical bone loss through a stimulatory effect of the PD-1/PD-L1 axis. Bone marrow adipocytes isolated from obese mice had increased Mcp-1 expression, a key regulator of osteoclastogenesis and myeloid cell accumulation. With the increase in bone marrow adipose tissue-derived Mcp-1, we found an increase in the number of PD-L1+ myeloid cells. While these cells inhibited activated T-cells, we found evidence of a stimulatory osteoclastogenic effect of PD-L1+ myeloid cells on PD-1-expressing osteoclast precursors. The inhibition of PD-1/PD-L1 signaling during early osteoclastogenesis prevented myeloid cell commitment and resulted in decreased cell fusion, supporting the role of PD-1/PD-L1 signaling in osteoclastogenesis. Using a bone marrow adipocyte depletion mouse model (BMAd-Pparg KO), we demonstrated that obese BMAd-Pparg KO mice had a reduced number of bone marrow PD-L1+ myeloid cells, accompanied by a decrease in PD-1+ osteoclast precursors. The reduction in these precursors resulted in fewer osteoclasts, subsequently leading to improved trabecular bone volume. Since osteoclasts are myeloid cell-derived, these results suggest that bone marrow adipocytes are critical for the commitment and differentiation of myeloid cells into osteoclasts. Targeting bone marrow adipogenesis could ameliorate enhanced osteoclastogenesis and provide a novel approach to treat obesity-related bone loss. Obesity-induced expansion of BM adipocytes leads to PD-1/PD-L1-driven osteoclastogenesis and subsequent bone loss in obese, HFD-fed (OB-HFD) mice. After 12 weeks on a HFD, OB-HFD mice had a significant increase in BM adiposity and BMAT-derived Mcp-1 expression. The increase in BMAT-specific Mcp-1 expression was coupled with an increase in PD-1+ osteoclast (OC) precursors and PD-L1+ myeloid cells. In the context of obesity, the PD-1/PD-L1 axis has a stimulatory effect that enhances osteoclastogenesis and leads to trabecular and cortical bone loss. By depleting BM adipocytes with obesity, BMAT-derived Mcp-1 expression was decreased, as well as a decrease in PD-1+ OC precursors and PD-L1+ myeloid cells. This prevented obesity-related trabecular bone loss. Overall, this work demonstrated a strong correlation between BMAT expansion and PD-1/PD-L1-driven osteoclastogenesis as a mechanism for obesity-induced bone loss. (This image was created using BioRender).

Bone marrow adipocytes are known to have a critical role within the bone marrow niche. However, our understanding of bone marrow adipose tissue expansion with obesity and the role it plays in immune cell regulation and osteoclastogenesis is limited. Here, we showed the expansion of bone marrow adipocytes promoted osteoclast differentiation and subsequently led to obesity-related trabecular and cortical bone loss through a stimulatory effect of the PD-1/PD-L1 axis. Bone marrow adipocytes isolated from obese mice had increased Mcp-1 expression, a key regulator of osteoclastogenesis and myeloid cell accumulation. With the increase in bone marrow adipose tissue-derived Mcp-1, we found an increase in the number of PD-L1+ myeloid cells. While these cells inhibited activated T-cells, we found evidence of a stimulatory osteoclastogenic effect of PD-L1+ myeloid cells on PD-1-expressing osteoclast precursors. The inhibition of PD-1/PD-L1 signaling during early osteoclastogenesis prevented myeloid cell commitment and resulted in decreased cell fusion, supporting the role of PD-1/PD-L1 signaling in osteoclastogenesis. Using a bone marrow adipocyte depletion mouse model (BMAd-Pparg KO), we demonstrated that obese BMAd-Pparg KO mice had a reduced number of bone marrow PD-L1+ myeloid cells, accompanied by a decrease in PD-1+ osteoclast precursors. The reduction in these precursors resulted in fewer osteoclasts, subsequently leading to improved trabecular bone volume. Since osteoclasts are myeloid cell-derived, these results suggest that bone marrow adipocytes are critical for the commitment and differentiation of myeloid cells into osteoclasts. Targeting bone marrow adipogenesis could ameliorate enhanced osteoclastogenesis and provide a novel approach to treat obesity-related bone loss. Obesity-induced expansion of BM adipocytes leads to PD-1/PD-L1-driven osteoclastogenesis and subsequent bone loss in obese, HFD-fed (OB-HFD) mice. After 12 weeks on a HFD, OB-HFD mice had a significant increase in BM adiposity and BMAT-derived Mcp-1 expression. The increase in BMAT-specific Mcp-1 expression was coupled with an increase in PD-1+ osteoclast (OC) precursors and PD-L1+ myeloid cells. In the context of obesity, the PD-1/PD-L1 axis has a stimulatory effect that enhances osteoclastogenesis and leads to trabecular and cortical bone loss. By depleting BM adipocytes with obesity, BMAT-derived Mcp-1 expression was decreased, as well as a decrease in PD-1+ OC precursors and PD-L1+ myeloid cells. This prevented obesity-related trabecular bone loss. Overall, this work demonstrated a strong correlation between BMAT expansion and PD-1/PD-L1-driven osteoclastogenesis as a mechanism for obesity-induced bone loss. (This image was created using BioRender).

Bone marrow adipocytes are known to have a critical role within the bone marrow niche. However, our understanding of bone marrow adipose tissue expansion with obesity and the role it plays in immune cell regulation and osteoclastogenesis is limited. Here, we showed the expansion of bone marrow adipocytes promoted osteoclast differentiation and subsequently led to obesity-related trabecular and cortical bone loss through a stimulatory effect of the PD-1/PD-L1 axis. Bone marrow adipocytes isolated from obese mice had increased Mcp-1 expression, a key regulator of osteoclastogenesis and myeloid cell accumulation. With the increase in bone marrow adipose tissue-derived Mcp-1, we found an increase in the number of PD-L1+ myeloid cells. While these cells inhibited activated T-cells, we found evidence of a stimulatory osteoclastogenic effect of PD-L1+ myeloid cells on PD-1-expressing osteoclast precursors. The inhibition of PD-1/PD-L1 signaling during early osteoclastogenesis prevented myeloid cell commitment and resulted in decreased cell fusion, supporting the role of PD-1/PD-L1 signaling in osteoclastogenesis. Using a bone marrow adipocyte depletion mouse model (BMAd-Pparg KO), we demonstrated that obese BMAd-Pparg KO mice had a reduced number of bone marrow PD-L1+ myeloid cells, accompanied by a decrease in PD-1+ osteoclast precursors. The reduction in these precursors resulted in fewer osteoclasts, subsequently leading to improved trabecular bone volume. Since osteoclasts are myeloid cell-derived, these results suggest that bone marrow adipocytes are critical for the commitment and differentiation of myeloid cells into osteoclasts. Targeting bone marrow adipogenesis could ameliorate enhanced osteoclastogenesis and provide a novel approach to treat obesity-related bone loss. Obesity-induced expansion of BM adipocytes leads to PD-1/PD-L1-driven osteoclastogenesis and subsequent bone loss in obese, HFD-fed (OB-HFD) mice. After 12 weeks on a HFD, OB-HFD mice had a significant increase in BM adiposity and BMAT-derived Mcp-1 expression. The increase in BMAT-specific Mcp-1 expression was coupled with an increase in PD-1+ osteoclast (OC) precursors and PD-L1+ myeloid cells. In the context of obesity, the PD-1/PD-L1 axis has a stimulatory effect that enhances osteoclastogenesis and leads to trabecular and cortical bone loss. By depleting BM adipocytes with obesity, BMAT-derived Mcp-1 expression was decreased, as well as a decrease in PD-1+ OC precursors and PD-L1+ myeloid cells. This prevented obesity-related trabecular bone loss. Overall, this work demonstrated a strong correlation between BMAT expansion and PD-1/PD-L1-driven osteoclastogenesis as a mechanism for obesity-induced bone loss. (This image was created using BioRender).

Bone marrow adipocytes are known to have a critical role within the bone marrow niche. However, our understanding of bone marrow adipose tissue expansion with obesity and the role it plays in immune cell regulation and osteoclastogenesis is limited. Here, we showed the expansion of bone marrow adipocytes promoted osteoclast differentiation and subsequently led to obesity-related trabecular and cortical bone loss through a stimulatory effect of the PD-1/PD-L1 axis. Bone marrow adipocytes isolated from obese mice had increased Mcp-1 expression, a key regulator of osteoclastogenesis and myeloid cell accumulation. With the increase in bone marrow adipose tissue-derived Mcp-1, we found an increase in the number of PD-L1+ myeloid cells. While these cells inhibited activated T-cells, we found evidence of a stimulatory osteoclastogenic effect of PD-L1+ myeloid cells on PD-1-expressing osteoclast precursors. The inhibition of PD-1/PD-L1 signaling during early osteoclastogenesis prevented myeloid cell commitment and resulted in decreased cell fusion, supporting the role of PD-1/PD-L1 signaling in osteoclastogenesis. Using a bone marrow adipocyte depletion mouse model (BMAd-Pparg KO), we demonstrated that obese BMAd-Pparg KO mice had a reduced number of bone marrow PD-L1+ myeloid cells, accompanied by a decrease in PD-1+ osteoclast precursors. The reduction in these precursors resulted in fewer osteoclasts, subsequently leading to improved trabecular bone volume. Since osteoclasts are myeloid cell-derived, these results suggest that bone marrow adipocytes are critical for the commitment and differentiation of myeloid cells into osteoclasts. Targeting bone marrow adipogenesis could ameliorate enhanced osteoclastogenesis and provide a novel approach to treat obesity-related bone loss. Obesity-induced expansion of BM adipocytes leads to PD-1/PD-L1-driven osteoclastogenesis and subsequent bone loss in obese, HFD-fed (OB-HFD) mice. After 12 weeks on a HFD, OB-HFD mice had a significant increase in BM adiposity and BMAT-derived Mcp-1 expression. The increase in BMAT-specific Mcp-1 expression was coupled with an increase in PD-1+ osteoclast (OC) precursors and PD-L1+ myeloid cells. In the context of obesity, the PD-1/PD-L1 axis has a stimulatory effect that enhances osteoclastogenesis and leads to trabecular and cortical bone loss. By depleting BM adipocytes with obesity, BMAT-derived Mcp-1 expression was decreased, as well as a decrease in PD-1+ OC precursors and PD-L1+ myeloid cells. This prevented obesity-related trabecular bone loss. Overall, this work demonstrated a strong correlation between BMAT expansion and PD-1/PD-L1-driven osteoclastogenesis as a mechanism for obesity-induced bone loss. (This image was created using BioRender).

Bone marrow adipocytes are known to have a critical role within the bone marrow niche. However, our understanding of bone marrow adipose tissue expansion with obesity and the role it plays in immune cell regulation and osteoclastogenesis is limited. Here, we showed the expansion of bone marrow adipocytes promoted osteoclast differentiation and subsequently led to obesity-related trabecular and cortical bone loss through a stimulatory effect of the PD-1/PD-L1 axis. Bone marrow adipocytes isolated from obese mice had increased Mcp-1 expression, a key regulator of osteoclastogenesis and myeloid cell accumulation. With the increase in bone marrow adipose tissue-derived Mcp-1, we found an increase in the number of PD-L1+ myeloid cells. While these cells inhibited activated T-cells, we found evidence of a stimulatory osteoclastogenic effect of PD-L1+ myeloid cells on PD-1-expressing osteoclast precursors. The inhibition of PD-1/PD-L1 signaling during early osteoclastogenesis prevented myeloid cell commitment and resulted in decreased cell fusion, supporting the role of PD-1/PD-L1 signaling in osteoclastogenesis. Using a bone marrow adipocyte depletion mouse model (BMAd-Pparg KO), we demonstrated that obese BMAd-Pparg KO mice had a reduced number of bone marrow PD-L1+ myeloid cells, accompanied by a decrease in PD-1+ osteoclast precursors. The reduction in these precursors resulted in fewer osteoclasts, subsequently leading to improved trabecular bone volume. Since osteoclasts are myeloid cell-derived, these results suggest that bone marrow adipocytes are critical for the commitment and differentiation of myeloid cells into osteoclasts. Targeting bone marrow adipogenesis could ameliorate enhanced osteoclastogenesis and provide a novel approach to treat obesity-related bone loss. Obesity-induced expansion of BM adipocytes leads to PD-1/PD-L1-driven osteoclastogenesis and subsequent bone loss in obese, HFD-fed (OB-HFD) mice. After 12 weeks on a HFD, OB-HFD mice had a significant increase in BM adiposity and BMAT-derived Mcp-1 expression. The increase in BMAT-specific Mcp-1 expression was coupled with an increase in PD-1+ osteoclast (OC) precursors and PD-L1+ myeloid cells. In the context of obesity, the PD-1/PD-L1 axis has a stimulatory effect that enhances osteoclastogenesis and leads to trabecular and cortical bone loss. By depleting BM adipocytes with obesity, BMAT-derived Mcp-1 expression was decreased, as well as a decrease in PD-1+ OC precursors and PD-L1+ myeloid cells. This prevented obesity-related trabecular bone loss. Overall, this work demonstrated a strong correlation between BMAT expansion and PD-1/PD-L1-driven osteoclastogenesis as a mechanism for obesity-induced bone loss. (This image was created using BioRender).

Bone marrow adipocytes are known to have a critical role within the bone marrow niche. However, our understanding of bone marrow adipose tissue expansion with obesity and the role it plays in immune cell regulation and osteoclastogenesis is limited. Here, we showed the expansion of bone marrow adipocytes promoted osteoclast differentiation and subsequently led to obesity-related trabecular and cortical bone loss through a stimulatory effect of the PD-1/PD-L1 axis. Bone marrow adipocytes isolated from obese mice had increased Mcp-1 expression, a key regulator of osteoclastogenesis and myeloid cell accumulation. With the increase in bone marrow adipose tissue-derived Mcp-1, we found an increase in the number of PD-L1+ myeloid cells. While these cells inhibited activated T-cells, we found evidence of a stimulatory osteoclastogenic effect of PD-L1+ myeloid cells on PD-1-expressing osteoclast precursors. The inhibition of PD-1/PD-L1 signaling during early osteoclastogenesis prevented myeloid cell commitment and resulted in decreased cell fusion, supporting the role of PD-1/PD-L1 signaling in osteoclastogenesis. Using a bone marrow adipocyte depletion mouse model (BMAd-Pparg KO), we demonstrated that obese BMAd-Pparg KO mice had a reduced number of bone marrow PD-L1+ myeloid cells, accompanied by a decrease in PD-1+ osteoclast precursors. The reduction in these precursors resulted in fewer osteoclasts, subsequently leading to improved trabecular bone volume. Since osteoclasts are myeloid cell-derived, these results suggest that bone marrow adipocytes are critical for the commitment and differentiation of myeloid cells into osteoclasts. Targeting bone marrow adipogenesis could ameliorate enhanced osteoclastogenesis and provide a novel approach to treat obesity-related bone loss. Obesity-induced expansion of BM adipocytes leads to PD-1/PD-L1-driven osteoclastogenesis and subsequent bone loss in obese, HFD-fed (OB-HFD) mice. After 12 weeks on a HFD, OB-HFD mice had a significant increase in BM adiposity and BMAT-derived Mcp-1 expression. The increase in BMAT-specific Mcp-1 expression was coupled with an increase in PD-1+ osteoclast (OC) precursors and PD-L1+ myeloid cells. In the context of obesity, the PD-1/PD-L1 axis has a stimulatory effect that enhances osteoclastogenesis and leads to trabecular and cortical bone loss. By depleting BM adipocytes with obesity, BMAT-derived Mcp-1 expression was decreased, as well as a decrease in PD-1+ OC precursors and PD-L1+ myeloid cells. This prevented obesity-related trabecular bone loss. Overall, this work demonstrated a strong correlation between BMAT expansion and PD-1/PD-L1-driven osteoclastogenesis as a mechanism for obesity-induced bone loss. (This image was created using BioRender).

The efficacy of combined chemotherapy and programmed cell death protein-1 (PD-1) immune checkpoint blockade (ICB) is constrained by the collateral cytotoxicity of chemotherapy toward proliferating tumor-specific CD8+ T (TTST) cells, a population indispensable for antitumor immunity. This study aimed to overcome this limitation by targeting a potential chemotherapy-resistant immune cell reservoir.

Antibody therapeutics have revolutionized cancer treatment, but their use is increasingly associated with adverse events. Among these, anaphylaxis is particularly concerning due to its severity and unpredictability. Our previous studies demonstrated that repeated administration of anti-programmed death-ligand 1 antibodies to tumor-bearing mice induces antidrug antibodies (ADAs) and anaphylaxis. However, the specific characteristics of antibody therapeutics responsible for this effect and the underlying mechanism of ADA production remain poorly understood. This study aimed to identify the immunological and molecular determinants of ADA-associated anaphylaxis following antibody therapeutics in tumor-bearing hosts.

Immune checkpoint blockade (ICB) faces limitations owing to high cost and restricted efficacy. This study identifies SNX17 as a key mediator of ICB resistance. Elevated SNX17 correlates with poor anti-PD-1 response in humans and mice. SNX17 deletion in tumor cells inhibits tumor growth via CD8+ T cell-dependent mechanisms. SNX17 reduces uridine in the tumor microenvironment (TME), suppressing IFN-γ and upregulating PD1 in CD8+ T cells. Exogenous uridine shows antitumor efficacy comparable to anti-PD-1/PD-L1 in low-SNX17 tumors and overcomes resistance in high-SNX17 models. Uridine enhances CD8+ T cell function by promoting CD45 N-glycosylation and LCK phosphorylation. Mechanistically, SNX17 stabilizes RUNX2, promoting UPP1 transcription and uridine degradation in the TME. These findings position SNX17 as an ICB response biomarker and nominate uridine as a cost-effective immunotherapeutic strategy.

Abnormal tumor vasculature greatly accelerates tumor progression and diminishes antitumor treatments. Restoring perivascular NO gradients is available to maintain tumor vessel homeostasis and promote tumor vascular normalization. However, exogenously delivering NO strategies lacks the durability to maintain precise NO localization around tumor vessels. Herein, we design a lipid nano delivery system (MC@L) and exploit endothelial transcytosis to deliver metformin (Met) and CaO2 into tumor vascular endothelial cells (ECs) and tumor cells for achieving tumor vascular normalization-boosted antitumor immunotherapies. The Ca2+ and Met released in ECs could restore perivascular localization of NO by activating endothelial NOS (eNOS). Additionally, MC@L internalized by tumor cells could cause CaO2-induced immunogenic cell death (ICD), together with hypoxia relief and acid neutralization mediated by O2 generation and H+ consumption during CaO2 degradation, thus further improving the immune effector cell functions under the accompaniment of Met-mediated inhibition of tryptophane uptake in tumor cells. Such a lipid nano delivery system greatly increases the susceptibility of 4T1 tumor-bearing mice to PD-L1 blockade efficacy.

Immunotherapy remains ineffective for a wide variety of solid tumors due to the existence of tumor immune evasion. Although the transcription factor ETV5 is recognized for its oncogenic roles in tumor progression, its role in remodeling the immunosuppressive microenvironment remains largely unexplored. Here, we reveal that tumor-intrinsic ETV5 drives immune evasion and immune checkpoint inhibitor (ICI) resistance by enhancing the expansion and recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Genetic silencing of ETV5 in murine tumor models suppressed PMN-MDSCs differentiation from myeloid progenitors, reduced their tumor infiltration, and attenuated immunosuppressive function, resulting in enhanced cytotoxic T cell activity and delayed tumor progression. Mechanistically, ETV5 directly binds to the JH1 domain of JAK2, inducing its dimerization and phosphorylation, which activates STAT3 to transcriptionally upregulate CCL2 and recruit PMN-MDSCs. Therapeutically, ETV5 ablation synergized with anti-PD-L1 therapy to enhance tumor control, mirroring clinical observations where high ETV5 expression predicted immunotherapy resistance. Our study uncovers a non-canonical, transcription-independent role of ETV5 in orchestrating the JAK2/STAT3/CCL2 axis to sustain PMN-MDSC-mediated immune evasion, proposing ETV5 as a druggable target to overcome ICI resistance in solid tumors.

Immune checkpoint blockade (ICB) evokes antitumor immunity through the reinvigoration of T cell responses. T cell differentiation status controls response, with less differentiated cells having an enhanced capacity to proliferate after ICB. Given that conventional type 1 dendritic cells (cDC1) maintain precursor exhausted T cells (TPEX), we hypothesized that expansion of cDC1s with Flt3L could enhance responses to ICB. Here we show that treatment with Fms-related tyrosine kinase 3 ligand (Flt3L) expands CD62L+SLAMF6+CD8+ T cells in the tumor through a mechanism that requires XCR1+ dendritic cells to traffic to the tumor-draining lymph node. The combination of Flt3L and anti-CTLA-4 enhanced therapeutic responses. Combination therapy is associated with the emergence of a CD8+ T cell subset characterized by the expression of Il21r and oligoclonal expansion of CD8+ T cells within tumors through a mechanism that is dependent on lymph node egress.

Adenosine-to-inosine (A-to-I) RNA editing, predominantly catalyzed by the enzyme adenosine deaminase acting on RNA 1 (ADAR1), has attracted interest due to its essential functions in regulating immune response and cancer progression. This research investigates ADAR1 inhibition as a promising strategy aimed at improving immunotherapy efficacy in lung adenocarcinoma (LUAD) and explores the underlying mechanisms. Findings from murine models demonstrate that ADAR1 suppression within tumors notably improves the immune microenvironment, marked by increased PD-L1 expression and enhanced CD8+ T-cell infiltration, as well as elevated levels of CXCL9, CXCL10, and CXCL11. These changes promote antitumor T-cell immune responses and amplify the effects of immunotherapy. Mechanistic investigations further reveal that deficiency in ADAR1 leads to an increase in double-stranded RNA (dsRNA), which serves as a substrate for A-to-I editing. This activates downstream signaling via dsRNA receptors, including RIG-I and MAVS, thereby inducing the IFN-β pathway. Significantly, IFN-β contributes to the ADAR1-dependent modulation of the tumor immune microenvironment and carcinogenesis in LUAD. Clinical validation in LUAD patients further confirms that reduced ADAR1 expression is associated with improved immunotherapy responses. These findings suggest inhibiting ADAR1-mediated A-to-I RNA editing is a promising approach to enhance the efficacy of immunotherapy in LUAD.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death, and patients usually exhibit impaired immune function within the tumor environment. NSD2 is an H3K36 methyltransferase and has been considered a cancer-promoting factor. However, the role of NSD2 in the occurrence and development of HCC is still unclear. In this study, the effects of NSD2 on HCC were assessed by both mouse and cell models. RNA-seq, ChIP-seq, and orthotopic tumor models were employed to decipher the downstream mechanisms of NSD2 responsible for HCC development. NSD2 alterations were characterized in patients with HCC. Hepatocyte-specific NSD2 overexpression suppresses the proliferation of tumor cells in DEN-treated mice. Mechanistically, NSD2 inhibits OXPHOS by activating target genes (Camk2d and Prkce) transcription. Downregulation of OXPHOS, caused by overexpression of NSD2, inhibits the expression of PD-L1 and enhances immune recognition of tumors. What's more, inhibition of OXPHOS suppresses the formation of HCC. Finally, patients with low expression of NSD2 have a better response to PD-L1 inhibitor treatment. These findings showed that NSD2 inhibits the progression of HCC by inhibiting the expression of PD-L1 through OXPHOS. Our results identify NSD2 as a tumor suppressor in the development of HCC.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death, and patients usually exhibit impaired immune function within the tumor environment. NSD2 is an H3K36 methyltransferase and has been considered a cancer-promoting factor. However, the role of NSD2 in the occurrence and development of HCC is still unclear. In this study, the effects of NSD2 on HCC were assessed by both mouse and cell models. RNA-seq, ChIP-seq, and orthotopic tumor models were employed to decipher the downstream mechanisms of NSD2 responsible for HCC development. NSD2 alterations were characterized in patients with HCC. Hepatocyte-specific NSD2 overexpression suppresses the proliferation of tumor cells in DEN-treated mice. Mechanistically, NSD2 inhibits OXPHOS by activating target genes (Camk2d and Prkce) transcription. Downregulation of OXPHOS, caused by overexpression of NSD2, inhibits the expression of PD-L1 and enhances immune recognition of tumors. What's more, inhibition of OXPHOS suppresses the formation of HCC. Finally, patients with low expression of NSD2 have a better response to PD-L1 inhibitor treatment. These findings showed that NSD2 inhibits the progression of HCC by inhibiting the expression of PD-L1 through OXPHOS. Our results identify NSD2 as a tumor suppressor in the development of HCC.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death, and patients usually exhibit impaired immune function within the tumor environment. NSD2 is an H3K36 methyltransferase and has been considered a cancer-promoting factor. However, the role of NSD2 in the occurrence and development of HCC is still unclear. In this study, the effects of NSD2 on HCC were assessed by both mouse and cell models. RNA-seq, ChIP-seq, and orthotopic tumor models were employed to decipher the downstream mechanisms of NSD2 responsible for HCC development. NSD2 alterations were characterized in patients with HCC. Hepatocyte-specific NSD2 overexpression suppresses the proliferation of tumor cells in DEN-treated mice. Mechanistically, NSD2 inhibits OXPHOS by activating target genes (Camk2d and Prkce) transcription. Downregulation of OXPHOS, caused by overexpression of NSD2, inhibits the expression of PD-L1 and enhances immune recognition of tumors. What's more, inhibition of OXPHOS suppresses the formation of HCC. Finally, patients with low expression of NSD2 have a better response to PD-L1 inhibitor treatment. These findings showed that NSD2 inhibits the progression of HCC by inhibiting the expression of PD-L1 through OXPHOS. Our results identify NSD2 as a tumor suppressor in the development of HCC.

Mesothelioma is a cancer derived from mesothelial cells, most commonly arising from the pleura or the peritoneum. Immune checkpoint therapy (ICT) has shown survival benefit for pleural mesothelioma, but little is known about the response in peritoneal mesothelioma. Most preclinical mesothelioma models involve subcutaneous cancer cell implantation, which lacks the relevant tumour microenvironment of peritoneal mesothelioma and does not resemble the clinical presentation. We therefore set out to explore the influence of location on the mesothelioma tumour microenvironment, comparing pleural, peritoneal, and subcutaneous models using identical cell line-derived syngeneic mesotheliomas. We found that the peritoneal location conferred an anti-inflammatory tumour microenvironment, characterised by low IFN, TNFα, and STAT signalling activity, low immune cell infiltration and a gene signature associated with non-response to ICT. ICT was effective in subcutaneous models, but the same cell line-derived tumours were irresponsive when inoculated intraperitoneally. Together, these findings show that peritoneal location is associated with an immune suppressive tumour microenvironment.

Most colorectal cancers (CRCs) are mismatch repair-proficient (pMMR) and microsatellite stable (MSS), and they respond poorly to immune checkpoint inhibitors (ICIs). Radiotherapy (RT) can promote antitumor immunity but may also trigger adaptive immune suppression through checkpoint upregulation, providing a rationale for combination therapies.