Immunotherapy faces significant challenges due to low clinical response rates and immune escape mechanisms, which ultimately lead to drug resistance. Previous studies suggest that adenosine-2A receptor (A2AR) signaling plays a critical role in immunosuppression and immune escape. However, no potent and selective A2AR inhibitors are currently available for clinical use to address immunotherapy resistance in tumors. In this study, we identified a novel small molecule compound, HZ-086, as a potent and selective inhibitor of A2AR. HZ-086 restored the activation of T-cell signaling which is suppressed by adenosine analogs in vitro. Additionally, HZ-086 enhanced T-cell-mediated cytotoxicity, increased the secretion of cytokines for antitumor and subsequently inhibited growth of tumor cells in vitro and in vivo. Furthermore, HZ-086 inhibited tumor growth, enhances anti-tumor capacity, and reversed PD-L1 resistance in vivo. When combined with FD-L1, a PD-L1 small molecule inhibitor discovered by our lab, HZ-086 achieved over 80 % tumor growth inhibition (TGI) and restored immune response in anti-PD-L1 monoclonal antibody-resistant tumors. This combination treatment also promoted the infiltration and activation of CD8+ T lymphocytes within the tumor microenvironment. Our findings demonstrate that adenosine-A2AR signaling mediates resistance to immunotherapy and discover a novel potent and selective A2AR inhibitor with high efficacy in enhancing antitumor immune responses and reversing PD-L1 resistance. The combination of A2AR inhibitor and PD-L1 inhibitor represents a promising therapeutic strategy for antitumor therapy.

Hypoxia serves as a critical determinant in the advancement of various intractable pathological conditions including oncological disorders and hypovascular wounds, which may profoundly attenuate the efficacy of pharmacological interventions and substantially inhibit the physiological recovery processes. Consequently, in an effort to mitigate the inherent constraints of conventional methodologies (e.g., exogenous oxygen delivery systems), a self-powered triboelectric nanogenerator (TENG)-based algae-integrated pliable and enveloped device (TAPED) operates as a wearable system to sustain oxygen generation. The TAPED system harnesses biomechanical energy generated through natural bodily movements to energize an integrated luminescent source, enabling controlled photosynthesis for sustained, on-demand oxygen production. The incorporation of TENG technology renders TAPED self-sufficient, eliminating the necessity for external recharging, reducing device mass, and improving convenience for continuous oxygen delivery. Additionally, its body-attachable design circumvents risks associated with direct algal implantation, such as immunogenic reactions and infections. Specifically, experimental application of TAPED has exhibited significant therapeutic efficacy in diverse pathological conditions, including diabetic chronic infected wounds, breast carcinoma tumors, and lactic acid accumulation consequent to strenuous exercise-induced fatigue. Collectively, the TAPED represents an advanced therapeutic approach, which holds substantial potential for translational application within clinical contexts, particularly for enhancing patient prognosis in hypoxic diseases such as oncology and wound management.

T cell engagers (TCEs) represent a groundbreaking advancement in the treatment of B and plasma cell malignancies and are emerging as a promising therapeutic approach for the treatment of solid tumors. These molecules harness T cells to bind to and eliminate cancer cells, effectively bypassing the need for antigen-specific T cell recognition. Despite their established clinical efficacy, a subset of patients is either refractory to TCE treatment (e.g. primary resistance) or develops resistance during the course of TCE therapy (e.g. acquired or treatment-induced resistance). In this review we comprehensively describe the resistance mechanisms to TCEs, occurring in both preclinical models and clinical trials with a particular emphasis on cellular and molecular pathways underlying the resistance process. We classify these mechanisms into tumor intrinsic and tumor extrinsic ones. Tumor intrinsic mechanisms encompass changes within tumor cells that impact the T cell-mediated cytotoxicity, including tumor antigen loss, the expression of immune checkpoint inhibitory ligands and intracellular pathways that render tumor cells resistant to killing. Tumor extrinsic mechanisms involve factors external to tumor cells, including the presence of an immunosuppressive tumor microenvironment (TME) and reduced T cell functionality. We further propose actionable strategies to overcome resistance offering potential avenues for enhancing TCE efficacy in the clinic.

Oxygen saturation imaging is a new technology that determines biological features from the perspective of oxygen concentration. Therefore, this exploratory study aimed to evaluate the biological implications of oxygen saturation imaging and further assess tumor heterogeneity in gastric cancer. Biopsy samples were selectively obtained from treatment-naïve patients with gastric cancer under real-time oxygen saturation imaging. Tissue oxygen saturation level calculations, immunohistochemistry, and RNA sequencing were performed. The mean tissue oxygen saturation levels at the sampling sites were 32.2%, 70.8%, and 56.2% for hypoxic, hyperoxic, and non-tumor areas, respectively, with significant differences between each pair. CD-31 and glucose transporter 1 protein expression were significantly upregulated in hypoxic tumors. Comprehensive transcriptomic analysis revealed enriched biological processes related to the regulation of insulin-like growth factor transport and uptake by insulin-like growth factor-binding proteins in hypoxic tumors and the type I interferon signaling pathway in hyperoxic tumors. Oxygen saturation imaging has the potential to clarify hypoxia-induced heterogeneity in gastric cancer from both clinical and fundamental perspectives.

Efforts to deconvolve the complex interactions of cancer cells with other components of the tumor micro- and macro-environment have exposed a common tendency for cancers to subvert systems physiology and exploit endogenous programs involved in homeostatic control of metabolism, immunity, regeneration, and repair. Many such programs are engaged in the healing response to surgery which, together with other abrupt biochemical changes in the perioperative period, provide an opportunity for the macroevolution of residual disease. This review relates contemporary perspectives of cancer as a systemic disease with the overlapping biology of host responses to surgery and events within the perioperative period. With a particular focus on examples of cancer cell plasticity and changes within the host, we explore how perioperative inflammation and acute metabolic, neuroendocrine, and immune dyshomeostasis might contribute to cancer evolution within this contextually short, yet crucially influential timeframe, and highlight potential therapeutic opportunities within to further optimize surgical cancer care and its long-term oncological outcomes.

Stimulating a robust cancer-immunity cycle (CIC) holds promising potential for eliciting potent and enduring immune responses for cancer immunotherapy. However, designing a therapeutic nanomaterial capable of both enhancing tumor immunogenicity and mitigating immunosuppression is challenging and often associated with complicated design paradigms and immune-related adverse effects. Herein, a multienzyme-mimetic alloy nanosheet incorporating palladium (Pd) and iron (Fe) is developed, which can prime effective CIC by overcoming ferroptosis resistance for enhancing tumor immunogenicity and reprograming the tumor microenvironment for enhanced second near-infrared (NIR-II) photoimmunotherapy. The nanosheets accumulate in tumors when administered intravenously and counteract hypoxia through catalase-like oxygen production and subsequent reduction of hypoxia-inducible factor-1α, M2-like macrophages, regulatory T-cell, and programmed death-ligand 1 (PD-L1) expression. The surface plasmon resonance of the nanosheets enables NIR-II phototherapy and photoacoustic imaging, coupling with its ferroptosis and tumor microenvironment reprogram properties to synergize with anti-PD-L1 checkpoint blockade therapy to achieve satisfactory antitumor outcome. This study offers a strategy for localized tumor treatment and boosting the CIC through a straightforward and inexpensive nanomaterial design.

Hypoxia/hypoxia-inducible factor 1α-driven immunosuppressive transcription and cAMP-elevating signaling through A2A adenosine receptors (A2ARs) represent a major tumor-protecting pathway that enables immune evasion. Recent promising clinical outcomes due to the blockade of the adenosine-generating enzyme CD73 and A2AR in patients refractory to all other therapies have confirmed the importance of targeting hypoxia-adenosinergic signaling. We report a feasible approach to target the upstream stage of hypoxia-adenosinergic immunosuppression using an oxygen-carrying nanoemulsion (perfluorocarbon blood substitute). We show that oxygenation agent therapy (a) eliminates tumor hypoxia, (b) improves efficacy of endogenously developed and adoptively transferred T cells, and thereby (c) promotes regression of tumors in different anatomical locations. We show that both T cells and NK cells avoid hypoxic tumor areas and that reversal of hypoxia by oxygenation agent therapy increases intratumoral infiltration of activated T cells and NK cells due to reprogramming of the tumor microenvironment (TME). Thus, repurposing oxygenation agents in combination with supplemental oxygen may improve current cancer immunotherapies by preventing hypoxia-adenosinergic suppression, promoting immune cell infiltration and enhancing effector responses. These data also suggest that pretreating patients with oxygenation agent therapy may reprogram the TME from immunosuppressive to immune-permissive prior to adoptive cell therapy, or other forms of immunotherapy.

Tumor hypoxia is a critical driver of cancer progression, metastasis, and therapy resistance, posing significant challenges in effective cancer treatment. Hypoxia-activable prodrugs offer a promising strategy to target tumors in low-oxygen conditions, but their efficacy is often hindered by intrinsic properties and extrinsic cues. In this study, we developed a dual-prodrug nanoassembly system (CPPA) composed of a hypoxia-triggerable camptothecin (CPT)-based dimeric prodrug (CP) and a lipid-conjugated STAT3 antisense oligonucleotide (ASO) prodrug (PA), aiming to enhance tumor-targeted chemotherapy and overcome the immune evasion within the tumor microenvironment. The CPPA self-assemble into stable nanomicelle capable of co-delivering both agents directly to the tumor site, where the hypoxia-triggered release of CPT induces immunogenic cell death (ICD) while STAT3 inhibition enhances immune response. In murine breast cancer models, CPPA demonstrated superior therapeutic efficacy by improving tumor cell killing, promoting immune cell infiltration, and modulating the immunosuppressive tumor microenvironment. This combination therapy not only reversed drug resistance but also prevented the formation of the pre-metastatic niche, significantly inhibiting tumor progression and metastasis. These findings highlight the potential of CPPA as an effective strategy for enhancing cancer immunotherapy, offering a promising approach to address the complex challenges of tumor hypoxia, immune evasion, and resistance to chemotherapy.

Hypoxia-related adenosine (Ado) exerts an immunosuppressive effect in tumors by binding to the metabolic checkpoint Ado A2A receptors (A2AR), thereby hindering the activation of antitumor immunity induced by immunogenic cell death (ICD). In this study, a MnO2-assisted photosynthetic bacteria (PSB) biohybrid (MnO2@PSB) is developed to enhance tumor photothermal immunotherapy by interfering with the Ado-A2AR metabolic pathway. Specifically, manganese dioxide (MnO2) nanoflowers are conjugated onto PSB by the carbodiimide reaction to construct the biohybrid MnO2@PSB. As a photothermal agent, MnO2@PSB generates heat to "burn" tumor cells under 808 nm laser irradiation, inducing tumor cell ICD. Meanwhile, MnO2@PSB catalyzes the decomposition of endogenous hydrogen peroxide into oxygen to alleviate tumor hypoxia, thereby reducing Ado production and downregulating the expression of A2AR, further reversing the tumor immunosuppressive microenvironment and amplifying the ICD effects. In various mouse 4T1 tumor models, MnO2@PSB can enhance antitumor immune responses, prolong mouse survival, and significantly inhibit tumor growth, recurrence, and metastasis under 808 nm laser irradiation. Collectively, this study provides a direction for enhanced antitumor immunotherapy through regulating metabolic pathways.

As important innate immune cells, natural killer (NK) cells play an essential role in resisting pathogen invasion and eliminating transformed cells. However, the hypoxic microenvironment caused by disease conditions is an important physicochemical factor that impairs NK cell function. With the increasing prominence of NK cells in immunotherapy, there has been a surge of interest in developing biological means through which NK cells may overcome the inhibition caused by hypoxia in disease conditions. Although the effects of hypoxic conditions in shaping the functions of NK cells have been increasingly recognized and investigated, reviews have been scantly. A comprehensive understanding of how NK cells adapt to hypoxia can provide valuable insights into how the functional capacity of NK cells may be restored. This review focuses on the functional alterations of NK cells in response to hypoxia. It delineates the mechanisms by which NK cells adapt to hypoxia at the transcriptional, metabolic, translational levels. Furthermore, given the complexity of the hypoxic microenvironment, we also elucidated the effects of key hypoxic metabolites on NK cells. Finally, this review discusses the current clinical therapies derived from targeting hypoxic NK cells. The study of NK cell adaptation to hypoxia has yielded new insights into immunotherapy. These insights may lead to development of novel strategies to improve the treatment of infectious diseases and cancer.

Immunotherapy has become a crucial strategy in cancer treatment, but its effectiveness is often constrained. Most cancer immunotherapies focus on stimulating T-cell-mediated immunity by driving the cancer-immunity cycle, which includes tumor antigen release, antigen presentation, T cell activation, infiltration, and tumor cell killing. However, metabolism reprogramming in the tumor microenvironment (TME) supports the viability of cancer cells and inhibits the function of immune cells within this cycle, presenting clinical challenges. The distinct metabolic needs of tumor cells and immune cells require precise and selective metabolic interventions to maximize therapeutic outcomes while minimizing adverse effects. Recent advances in nanotherapeutics offer a promising approach to target tumor metabolism reprogramming and enhance the cancer-immunity cycle through tailored metabolic modulation. In this review, we explore cutting-edge nanomaterial strategies for modulating tumor metabolism to improve therapeutic outcomes. We review the design principles of nanoplatforms for immunometabolic modulation, key metabolic pathways and their regulation, recent advances in targeting these pathways for the cancer-immunity cycle enhancement, and future prospects for next-generation metabolic nanomodulators in cancer immunotherapy. We expect that emerging immunometabolic modulatory nanotechnology will establish a new frontier in cancer immunotherapy in the near future.

Consolidation with PD-1/PD-L1-based immune checkpoint blockade after concurrent platinum-based chemo-radiotherapy has become the new standard of care for advanced stage III unresectable non-small cell lung cancer (NSCLC) patients. In order to further improve therapy outcomes, innovative combinatorial treatment strategies aim to target additional immunosuppressive barriers in the tumor microenvironment such as the CD73/adenosine pathway. CD73 and adenosine are known as crucial endogenous regulators of lung homeostasis and inflammation, but also contribute to an immunosuppressive tumor microenvironment. Furthermore, the CD73/adenosine pathway can also limit the immune-activating effects of cytotoxic therapies by degrading the pro-inflammatory danger molecule ATP, which is released into the tumor microenvironment and normal lung tissue upon therapy-induced cell damage. Thus, while targeting CD73 may enhance the efficacy of radio-immunotherapies in cancer treatment by mitigating tumor immune escape and improving immune-mediated tumor killing, it also raises concerns about increased immune-related adverse events (irAEs) in the normal tissue. In fact, combined radio-immunotherapies bear an increased risk of irAEs in the lungs, and additional pharmacologic inhibition of CD73 may further enhance the risk of overwhelming or overlapping pulmonary toxicity and thereby limit therapy outcome. This review explores how therapeutic interventions targeting CD73/adenosine dynamics could enhance radiation-induced immune activation in combined radio-immunotherapies, whilst potentially driving irAEs in the lung. We specifically investigate the interactions between radiotherapy and the CD73/adenosine pathway in radiation pneumonitis. Additionally, we compare the incidence of (radiation) pneumonitis reported in relevant trials to determine if there is an increased risk of irAEs in the clinical setting. By understanding these dynamics, we aim to inform future strategies for optimizing radio-immunotherapy regimens, ensuring effective cancer control while preserving pulmonary integrity and patient quality of life.

Tumor tissues exhibit significantly lower oxygen partial pressure compared to normal tissues, leading to hypoxia in the tumor microenvironment and result in resistance to tumor treatments. Strategies to mitigate hypoxia include enhancing blood perfusion and oxygen supply, for example,by decomposing hydrogen peroxide within the tumor. Improving hypoxia in the tumor microenvironment could potentially improve the efficacy of cancer treatments. Previous studies have demonstrated that ultrasound of appropriate intensity when combined with microbubbles, can improve tumor blood perfusion. However, its effects on tumor hypoxia remain unclear. This study aimed to assess the effects of low-frequency non-focused ultrasound combined with microbubbles at different intensities on tumor microenvironment hypoxia and to identify the optimal ultrasound parameters for alleviating tumor hypoxia.

Rabbits with VX2 tumors received ultrasound and microbubble treatments at different acoustic pressures and pulse repetition frequencies. The changes in tumor tissue blood perfusion before and after treatment were observed by contrast enhanced ultrasound (CEUS). The changes in tumor tissue hypoxia before and after treatment were observed by measuring oxygen partial pressure directly with in tumor tissue and immunohistochemical staining for hypoxia-inducible factor-1α (HIF-1α).

Results indicated that low frequency, non-focused ultrasound at 0.5 MPa/20 Hz and 0.5 MPa/40 Hz, when combined with microbubbles, could increase tumor tissue blood perfusion and improve the hypoxia in tumor tissues.

This study provides a new method for improving hypoxia in the tumor microenvironment (TME) which could potentially improve the cancer treatments resistance.

Despite the established use of immune checkpoint inhibitors (ICIs) to treat non-small cell lung cancer (NSCLC), only a subset of patients benefit from treatment and ∼50% of patients whose tumors respond eventually develop acquired resistance (AR). To identify novel drivers of AR, we generated murine Msh2 knock-out (KO) lung tumors that initially responded but eventually developed AR to anti-PD-1, alone or in combination with anti-CTLA-4. Resistant tumors harbored decreased infiltrating T cells and reduced cancer cell-intrinsic MHC-I and MHC-II levels, yet remained responsive to IFNγ. Resistant tumors contained extensive regions of hypoxia, and a hypoxia signature derived from single-cell transcriptional profiling of resistant cancer cells was associated with decreased progression-free survival in a cohort of NSCLC patients treated with anti-PD-1/PD-L1 therapy. Targeting hypoxic tumor regions using a hypoxia-activated pro-drug delayed AR to ICIs in murine Msh2 KO tumors. Thus, this work provides a rationale for targeting tumor metabolic features, such as hypoxia, in combination with immune checkpoint inhibition.

Conventional chemotherapy- and radiotherapy-induced cancer senescence, which is characterized by poor proliferation, drug resistance, and senescence-associated secretory phenotype, has gained attention as contributing to cancer relapse and the development of an immunosuppressive tumor microenvironment. However, the association between cancer senescence and anti-tumor immunity is not fully understood. Here, we demonstrate that senescent cancer cells increase the level of PD-L1 by promoting its transcription and glycosylation. We identify ribophorin 1 as a key regulator of PD-L1 glycosylation during cancer senescence. Ribophorin 1 depletion reduces this elevated level of PD-L1 through the ER-lysosome-associated degradation pathway, thereby increasing the susceptibility of senescent cancer cells to T-cell-mediated killing. Consistently, ribophorin 1 depletion suppresses tumor growth by decreasing PD-L1 levels and boosting cytotoxic T lymphocyte activity in male mice. Moreover, ribophorin 1-targeted or anti-PD-1 therapy reduces the number of senescent cancer cells in irradiated tumors and suppresses cancer recurrence through the activation of cytotoxic T lymphocytes. These results provide crucial insights into how senescent cancer cells can escape T-cell immunity following cancer treatment and thereby contribute to cancer recurrence. Our findings also highlight the therapeutic promise of targeting senescent cancer cells for cancer treatment.

Immunotherapy has transformed current cancer management, and it has achieved significant progress over last decades. However, an immunosuppressive tumor microenvironment (TME) diminishes the effectiveness of immunotherapy by suppressing the activity of immune cells and facilitating tumor immune-evasion. Adenosine monophosphate-activated protein kinase (AMPK), a key modulator of cellular energy metabolism and homeostasis, has gained growing attention in anti-tumor immunity. Metformin is usually considered as a cornerstone in diabetes management, and its role in activating the AMPK pathway has also been extensively explored in cancer therapy although the findings on its role remain inconsistent. Metformin in a nanomedicine formulation has been found to hold potential in reprogramming the immunosuppressive TME through immunometabolic modulation of both tumor and immune cells. This review elaborates the foundation and progress of immunometabolic reprogramming of the TME via metformin-based nanomedicines, offering valuable insights for the next generation of cancer therapy.

Programmed death (PD) 1/PD ligand 1 (PDL1) inhibitors are immune checkpoint inhibitors (ICIs) that may facilitate HER2-positive breast cancer treatment; however, their clinical efficacy remains elusive. Oxygen-enhanced photodynamic therapy (PDT) increases immunogenic cell death (ICD), providing a promising strategy to render the tumor microenvironment more sensitive to the ICIs. Lipid-encapsulated oxygen nanobubbles (Lipo-NBs-O2) obtained using nanobubbles (NBs) water for oxygen delivery in vivo can facilitate enhanced PDT. Here, dual-receptor targeted Lipo-NBs-O2 (DRT@Lipo-NBs-O2) is prepared by modifying Lipo-NBs-O2 with anti-PDL1 scFv and the fusion protein anti-HER2 scFv-tandem-repeat cytochrome c (anti-HER2-nCytc). Copper phthalocyanine is the photosensitizer (PS). DRT@Lipo-PS-NBs-O2 plus near-infrared irradiation leads to robust ICD induction, increasing DC activation and CD8+ T-cell numbers. Modification with anti-PDL1 scFv improves tumor distribution of DRT@Lipo-PS-NBs-O2 and plays the ICI role, invigorating CD8+ T cells and boosting the effects of immunotherapy. Oxygen supplied through DRT@Lipo-PS-NBs-O2 reduces P-glycoprotein expression. Enhanced PDT and Cytc can cause tumor cell death, thereby reducing the immune burden. Under dual receptor targeting and laser local irradiation, tumor cells become subject to the combination effects of PDT, ICD, ICIs, and apoptosis; this effectively suppresses tumor growth and metastasis. Lipo-NBs-O2 affords a combination of oxygen delivery and multidrug therapy to alleviate HER2-positive breast cancer.

Tumor metastasis is the primary cause of cancer-related mortality and remains a major hurdle in cancer treatment. Traditional cigarette smoking has been extensively studied for its role in promoting metastasis. However, the impact of e-cigarette (e-cig) on cancer metastasis is not well understood despite their increasing popularity as a supposedly safer alternative. This mini review synthesizes current literature on the effects of e-cig on cancer metastasis, focusing on the processes of dissemination, dormancy, and colonization. It also incorporates recent findings from our laboratory regarding the role of e-cig in tumor progression. E-cig exposure enhances metastatic potential through various mechanisms: it induces epithelial-mesenchymal transition (EMT), increasing cell migratory and invasive capabilities; promotes lymphangiogenesis, aiding tumor cell spread; and alters the pre-metastatic niche to support dormant tumor cells, enhancing their reactivation and colonization. Furthermore, e-cig induce significant epigenetic changes, such as DNA methylation and histone modifications, which regulate genes involved in metastasis. Our data suggest that e-cig upregulate histone demethylases like KDM6B in macrophages, impacting the TME and promoting metastasis. These findings underscore the need for further research to understand the long-term health implications of e-cig use and inform public health policies to reduce e-cig use.

Hypoxia can drive tumor progression, suppress anti-tumor immunity, and reduce the effectiveness of radiotherapy and chemotherapy. This study aimed to assess the impact of remote ischemic conditioning (RIC) on tumor oxygenation (sO2) and the anti-tumor immune response.

Fourteen B16-Ova tumor-bearing C57BL/6N mice received six 5-minute RIC cycles, while another fourteen underwent anesthesia only. Pimonidazole was administered 1.5 hours before sacrifice. Blood flow, sO2, and hemoglobin levels were measured in the non-ischemic hind limb and tumor. Tumor hypoxia was assessed using pimonidazole and CA IX immunohistochemistry, and T cell infiltration by CD3 and FoxP3 staining. Serum levels of 23 cytokines were analyzed using a multiplex immunoassay.

Isoflurane anesthesia caused a slight intraindividual increase in blood flow (p = 0.07) and sO2 (p = 0.06) of the hind limb and a sole increase in tumor sO2 (p = 0.035), whereas RIC improved sO2 of the tumor in relation to the hind limb (p=0.03). The median of the tumor oxygen saturation reached 51.4% in the control group and 62.7% in the RIC group (p = 0.09), exhibiting a slight tendency towards better oxygenation in the RIC group. Pimonidazole (p=0.24) and CA IX hypoxia score (p=0.48) did not reveal statistically significant differences between the two groups. In RIC-treated tumors, the number of CD3 (p=0.006), but not FoxP3- positive cells (p = 0.84), in the tumor core was significantly higher compared to the control group. In the RIC group, the mean fluorescence intensity (MFI) of IL-17 was significantly higher (p=0.035), and TNF-α was trend-wise higher (p=0.063) compared to the control group.

Both isoflurane anesthesia and RIC have an impact on microcirculation. The application of RIC counteracted some of the effects of isoflurane, primarily in healthy tissue, and led to a significant improvement in relative tumor tissue oxygenation compared to the non-ischemic hind limb. RIC selectively enhanced immune infiltration within the tumor center, probably by previously activated tumor infiltrating T cells, while having no significant impact on T-regulatory cells. RIC appears to impact the cytokine profile, as indicated by elevated MFIs of TNF-α and IL-17.

Hypoxic microenvironments induce widespread metabolic changes that have been shown to be critical in regulating innate and adaptive immune responses. Hypoxia-induced changes include the generation of extracellular adenosine followed by subsequent signaling through adenosine receptors on immune cells. This evolutionarily conserved "hypoxia-adenosinergic" pathway of hypoxia → extracellular adenosine → adenosine receptor signaling has been shown to be critical in limiting and redirecting T cell responses including in tumor microenvironments and the gut mucosa. However, the question of whether hypoxic microenvironments are involved in the development of B cell responses has remained unexplored until recently. The discovery that germinal centers (GC), the anatomic site in which B cells undergo secondary diversification and affinity maturation, develop a hypoxic microenvironment has sparked new interest in how this evolutionarily conserved pathway affects antibody responses. In this review we will summarize what is known about hypoxia-adenosinergic microenvironments in lymphocyte development and ongoing immune responses. Specific focus will be placed on new developments regarding the role of the hypoxia-adenosinergic pathway in regulating GC development and humoral immunity.

The tumor microenvironment (TME) orchestrates a complex interplay between tumor cells and immune cells, crucially modulating the immune response. This review delves into the pivotal role of metabolic reprogramming in the TME, highlighting how tumor-derived metabolites influence T lymphocyte functionality and the efficacy of cancer immunotherapies. Focusing on the diverse roles of these metabolites, we examine how lactate, lipids, amino acids, and other biochemical signals act not only as metabolic byproducts but as regulatory agents that can suppress or potentiate T cell-mediated immunity. By integrating recent findings, we underscore the dual impact of these metabolites on enhancing tumor progression and inhibiting immune surveillance. Furthermore, we propose innovative therapeutic strategies that target metabolic pathways to restore immune function within the TME. The insights provided in this review pave the way for the development of metabolic interventions aimed at enhancing the success of immunotherapies in oncology, offering new hope for precision medicine in the treatment of cancer.

Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis that is associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIF). Identification of the long-lasting effects of hypoxia beyond the immediate HIF-induced alterations could provide a better understanding of hypoxia-driven metastasis and potential strategies to circumvent it. Here, we uncovered a hypoxia-induced mechanism that exerts a prolonged effect to promote metastasis. In breast cancer patient-derived circulating tumor cell lines and common breast cancer cell lines, hypoxia downregulated tumor-intrinsic type I IFN signaling and its downstream antigen presentation (AP) machinery in luminal breast cancer cells, via both HIF-dependent and HIF-independent mechanisms. Hypoxia induced durable IFN/AP suppression in certain cell types that was sustained after returning to normoxic conditions, presenting a "hypoxic memory" phenotype. Hypoxic memory of IFN/AP downregulation was established by specific hypoxic priming, and cells with hypoxic memory had an enhanced ability for tumorigenesis and metastasis. Overexpression of IRF3 enhanced IFN signaling and reduced tumor growth in normoxic, but not hypoxic, conditions. The histone deacetylase inhibitor entinostat upregulated IFN targets and erased the hypoxic memory. These results point to a mechanism by which hypoxia facilitates tumor progression through a long-lasting memory that provides advantages for circulating tumor cells during the metastatic cascade. Significance: Long-term cellular memory of hypoxia leads to sustained suppression of tumor-intrinsic type I IFN signaling and the antigen presentation pathway that facilitates tumorigenesis and metastasis. See related commentary by Purdy and Ford, p. 3125.

This review critically evaluates the substantial role of exercise in enhancing cancer prevention, treatment, and patient quality of life. It conclusively demonstrates that regular physical activity not only reduces cancer risk but also significantly mitigates side effects of cancer therapies. The key findings include notable improvements in fatigue management, reduction of cachexia symptoms, and enhancement of cognitive functions. Importantly, the review elucidates the profound impact of exercise on tumor behavior, modulation of immune responses, and optimization of metabolic pathways, advocating for the integration of exercise into standard oncological care protocols. This refined abstract encourages further exploration and application of exercise as a pivotal element of cancer management.

Due to its anti-angiogenic properties, trebananib is frequently employed in the treatment of cancer patients, particularly those with ovarian cancer. We conducted a meta-analysis to assess the efficacy and safety profile of trebananib in combination with other drugs for treating both ovarian and non-ovarian cancer patients.

Our search encompassed PubMed, Medline, Cochrane, and Embase databases, with a focus on evaluating study quality. Data extraction was conducted from randomized controlled trials (RCTs), and RevMan 5.3 facilitated result analysis.

Combining trebananib with other drugs extended progression-free survival (PFS) [HR 0.81, (95%CI: 0.65, 0.99), p = 0.04] and overall survival (OS) [HR 0.88, (95%CI: 0.79, 1.00), p = 0.04] in ovarian cancer patients. Ovarian cancer patients exhibited a higher objective response rate (ORR) with trebananib compared to non-ovarian cancer cohorts. Moreover, the incorporation of trebananib into the standard treatment regimen for malignant tumors did not significantly elevate drug-related adverse events [RR 1.05, (95% CI: 1.00, 1.11), p = 0.05].

Trebananib plus other drugs can improve the PFS, OS and ORR in patients with cancer, especially ovarian cancer. Our recommendation is to use trebananib plus other drugs to treat advanced cancer, and to continuously monitor and manage drug-related adverse events.

PROSPERO (No. CRD42023466988).

Adoptive cell transfer (ACT) is a therapeutic strategy to augment antitumor immunity. Here, we report that ex vivo treatment of mouse CD8+ T cells with dimethyloxalylglycine (DMOG), a stabilizer of hypoxia-inducible factors (HIFs), induced HIF binding to the genes encoding the costimulatory receptors CD81, GITR, OX40, and 4-1BB, leading to increased expression. DMOG treatment increased T cell killing of melanoma cells, which was further augmented by agonist antibodies targeting each costimulatory receptor. In tumor-bearing mice, ACT using T cells treated ex vivo with DMOG and agonist antibodies resulted in decreased tumor growth compared to ACT using control T cells and increased intratumoral markers of CD8+ T cells (CD7, CD8A, and CD8B1), natural killer cells (NCR1 and KLRK1), and cytolytic activity (perforin-1 and tumor necrosis factor-α). Costimulatory receptor gene expression was also induced when CD8+ T cells were treated with three highly selective HIF stabilizers that are currently in clinical use.

Extracellular adenosine (eAdo) bridges tumor metabolism and immune regulation. CD39-CD73-eAdo/A2aR axis regulates tumor microenvironment (TME) and immunotherapy response. In the era of immunotherapy, exploring the impact of the CD39-CD73-eAdo/A2aR axis on TME and developing targeted therapeutic drugs to enhance the efficacy of immunotherapy are the current research hotspots. This study summarizes and explores the research trends and hotspots of the adenosine axis in the field of TME to provide ideas for further in-depth research.

Literature information was obtained from the Web of Science core collection database. The VOS viewer and the bibliometric tool based on R were used to quantify and identify cooperation information and individual influence by analyzing the detailed information of the global annual publication volume, country/region and institution distribution, article authors and co-cited authors, and journal distribution of these articles. At the same time, the distribution of author keywords and the co-occurrence of author keywords, highly cited articles, and highly co-cited references of CD39-CD73-eAdo/A2aR in the field of TME were analyzed to determine research hotspots and trends.

1,721 articles published in the past ten years were included in this study. Through bibliometric analysis, we found that (1) 69 countries and regions explored the effect of the CD39-CD73-eAdo/A2aR on TME, and the research was generally on the rise. Researchers in the United States dominated research in this area, with the highest total citation rate. China had the most significant number of publications. (2) Harvard University has published the most articles in this field. (3) 12,065 authors contributed to the publication of papers in this field, of which 23 published at least eight papers. STAGG J had significant academic influence, with 24 published articles and 2,776 citations. Co-cited authors can be clustered into three categories. Stagg J, Allard B, Ohta A, and Antonioli, L occupied a central position in the network. (4) 579 scholarly journals have published articles in this field. The journal FRONTIERS IN IMMUNOLOGY published the most significant number of papers, with 97 articles and a total of 2,317 citations, and the number of publications increased year by year. (5) "The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets" was the most frequently local cited article (163 times). The "A2A adenosine receptor protects tumors from antitumor T cells" was the most co-cited reference (224 times). (6) Through the analysis of author keywords, we found that the relationship between adenosine and immunotherapy was a core concept for many researchers in this field. Breast cancer, melanoma, colorectal cancer, ovarian cancer, glioblastoma, pancreatic cancer, hepatocellular carcinoma, and lung cancer were the most frequent cancer types in adenosine-related tumor studies. Immunotherapy, immunosuppression, immune checkpoint, and immune checkpoint inhibitors were the hot keywords in the research, reflecting the importance of the adenosine metabolic pathway in tumor immunotherapy. The keywords such as Immunogenic cell death, T cells, Sting, regulatory T cells, innate immunity, and immune infiltration demonstrated the pathways by which adenosine affected the TME. The famous author keywords in recent years have been immunotherapy, immunogenic cell death, inflammation, lung cancer, and gastric cancer.

The effect of CD39-CD73-eAdo/A2aR on the infiltration and function of various immune cells in TME, tumor immunotherapy response, and patient prognosis has attracted the attention of researchers from many countries/regions. American scholars still dominate the research in this field, but Chinese scholars produce the most research results. The journal FRONTIERS IN IMMUNOLOGY has published the wealthiest research in the field. Stagg J was a highly influential researcher in this field. Further exploration of targeted inhibition of CD39-CD73-eAdo/A2aR alone or in combination with other immunotherapy, radiotherapy, and chemotherapy in treating various cancer types and developing effective clinical therapeutic drugs are continuous research hotspots in this field.

In oxygen (O2)-controlled cell culture, an indispensable tool in biological research, it is presumed that the incubator setpoint equals the O2 tension experienced by cells (i.e., pericellular O2). However, it is discovered that physioxic (5% O2) and hypoxic (1% O2) setpoints regularly induce anoxic (0% O2) pericellular tensions in both adherent and suspension cell cultures. Electron transport chain inhibition ablates this effect, indicating that cellular O2 consumption is the driving factor. RNA-seq analysis revealed that primary human hepatocytes cultured in physioxia experience ischemia-reperfusion injury due to cellular O2 consumption. A reaction-diffusion model is developed to predict pericellular O2 tension a priori, demonstrating that the effect of cellular O2 consumption has the greatest impact in smaller volume culture vessels. By controlling pericellular O2 tension in cell culture, it is found that hypoxia vs. anoxia induce distinct breast cancer transcriptomic and translational responses, including modulation of the hypoxia-inducible factor (HIF) pathway and metabolic reprogramming. Collectively, these findings indicate that breast cancer cells respond non-monotonically to low O2, suggesting that anoxic cell culture is not suitable for modeling hypoxia. Furthermore, it is shown that controlling atmospheric O2 tension in cell culture incubators is insufficient to regulate O2 in cell culture, thus introducing the concept of pericellular O2-controlled cell culture.

Cancer is a significant global health issue that poses a considerable burden on both patients and healthcare systems. Many different types of cancers exist that often require unique treatment approaches and therapies. A hallmark of tumor progression is the creation of an immunosuppressive environment, which poses complex challenges for current treatments. Amongst the most explored characteristics is a hypoxic environment, high interstitial pressure, and immunosuppressive cells and cytokines. Traditional cancer treatments involve radiotherapy, chemotherapy, and surgical procedures. The advent of immunotherapies was regarded as a promising approach with hopes of greatly increasing patients' survival and outcome. Although some success is seen with various immunotherapies, the vast majority of monotherapies are unsuccessful. This review examines how various aspects of the tumor microenvironment (TME) present challenges that impede the success of immunotherapies. Subsequently, we review strategies to manipulate the TME to facilitate the success of immunotherapies.

Tumor metastasis is the primary cause of cancer-related deaths. The prevention of tumor metastasis has garnered notable interest and interrupting metastatic biological processes is considered a potential strategy for preventing tumor metastasis. The tumor microenvironment (TME), circulating tumor cells (CTCs), and premetastatic niche (PMN) play crucial roles in metastatic biological processes. These processes can be interrupted using nanomaterials due to their excellent physicochemical properties. However, most studies have focused on only one aspect of tumor metastasis. Here, the hypothesis that nanomaterials can be used to target metastatic biological processes and explore strategies to prevent tumor metastasis is highlighted. First, the metastatic biological processes and strategies involving nanomaterials acting on the TME, CTCs, and PMN to prevent tumor metastasis are briefly summarized. Further, the current challenges and prospects of nanomaterials in preventing tumor metastasis by interrupting metastatic biological processes are discussed. Nanomaterial-and multifunctional nanomaterial-based strategies for preventing tumor metastasis are advantageous for the long-term fight against tumor metastasis and their continued exploration will facilitate rapid progress in the prevention, diagnosis, and treatment of tumor metastasis. Novel perspectives are outlined for developing more effective strategies to prevent tumor metastasis, thereby improving the outcomes of patients with cancer.

Glioblastoma (GBM) tumors are the most aggressive primary brain tumors in adults that, despite maximum treatment, carry a dismal prognosis. GBM tumors exhibit tissue hypoxia, which promotes tumor aggressiveness and maintenance of glioma stem cells and creates an overall immunosuppressive landscape. This article reviews how hypoxic conditions overlap with inflammatory responses, favoring the proliferation of immunosuppressive cells and inhibiting cytotoxic T cell development. Immunotherapies, including vaccines, immune checkpoint inhibitors, and CAR-T cell therapy, represent promising avenues for GBM treatment. However, challenges such as tumor heterogeneity, immunosuppressive TME, and BBB restrictiveness hinder their effectiveness. Strategies to address these challenges, including combination therapies and targeting hypoxia, are actively being explored to improve outcomes for GBM patients. Targeting hypoxia in combination with immunotherapy represents a potential strategy to enhance treatment efficacy.

Mitophagy serves as a critical mechanism for tumor cell death, significantly impacting the progression of tumors and their treatment approaches. There are significant challenges in treating patients with head and neck squamous cell carcinoma, underscoring the importance of identifying new targets for therapy. The function of mitophagy in head and neck squamous carcinoma remains uncertain, thus investigating its impact on patient outcomes and immunotherapeutic responses is especially crucial. We initially analyzed the differential expression, prognostic value, intergene correlations, copy number variations, and mutation frequencies of mitophagy-related genes at the pan-cancer level. Through unsupervised clustering, we divided head and neck squamous carcinoma into three subtypes with distinct prognoses, identified the signaling pathway features of each subtype using ssGSEA, and characterized subtype B as having features of an immune desert using various immune infiltration calculation methods. Using multi-omics data, we identified the genomic variation characteristics, mutated gene pathway features, and drug sensitivity features of the mitophagy subtypes. Utilizing a combination of 10 machine learning algorithms, we have developed a prognostic scoring model called Mitophagy Subgroup Risk Score (MSRS), which is used to predict patient survival and the response to immune checkpoint blockade therapy. Simultaneously, we applied MSRS to single-cell analysis to explore intercellular communication. Through laboratory experiments, we validated the biological function of SLC26A9, one of the genes in the risk model. In summary, we have explored the significant role of mitophagy in head and neck tumors through multi-omics data, providing new directions for clinical treatment.

Patients with chronic hypoxia show a higher tumor incidence; however, no primary common cause has been recognized. Given the similarities between cellular reprogramming and oncogenic transformation, we directly compared these processes in human cells subjected to hypoxia. Mouse embryonic fibroblasts were employed as controls to compare transfection and reprogramming efficiency; human adipose-derived mesenchymal stem cells were employed as controls in human cells. Easily obtainable human peripheral blood mononuclear cells (PBMCs) were chosen to establish a standard protocol to compare cell reprogramming (into induced pluripotent stem cells (iPSCs)) and oncogenic focus formation efficiency. Cell reprogramming was achieved for all three cell types, generating actual pluripotent cells capable for differentiating into the three germ layers. The efficiencies of the cell reprogramming and oncogenic transformation were similar. Hypoxia slightly increased the reprogramming efficiency in all the cell types but with no statistical significance for PBMCs. Various PBMC types can respond to hypoxia differently; lymphocytes and monocytes were, therefore, reprogrammed separately, finding a significant difference between normoxia and hypoxia in monocytes in vitro. These differences were then searched for in vivo. The iPSCs and oncogenic foci were generated from healthy volunteers and patients with chronic obstructive pulmonary disease (COPD). Although higher iPSC generation efficiency in the patients with COPD was found for lymphocytes, this increase was not statistically significant for oncogenic foci. Remarkably, a higher statistically significant efficiency in COPD monocytes was demonstrated for both processes, suggesting that physiological hypoxia exerts an effect on cell reprogramming and oncogenic transformation in vivo in at least some cell types.

To explore the cellular cross-talk of tumor-resident mast cells (MC) in controlling the activity of cancer-associated fibroblasts (CAF) to overcome tumor microenvironment (TME) abnormalities, enhancing the efficacy of immune-checkpoint inhibitors in sarcoma.

We used a coculture system followed by further validation in mouse models of fibrosarcoma and osteosarcoma with or without administration of the MC stabilizer and antihistamine ketotifen. To evaluate the contribution of ketotifen in sensitizing tumors to therapy, we performed combination studies with doxorubicin chemotherapy and anti-PD-L1 (B7-H1, clone 10F.9G2) treatment. We investigated the ability of ketotifen to modulate the TME in human sarcomas in the context of a repurposed phase II clinical trial.

Inhibition of MC activation with ketotifen successfully suppressed CAF proliferation and stiffness of the extracellular matrix accompanied by an increase in vessel perfusion in fibrosarcoma and osteosarcoma as indicated by ultrasound shear wave elastography imaging. The improved tissue oxygenation increased the efficacy of chemoimmunotherapy, supported by enhanced T-cell infiltration and acquisition of tumor antigen-specific memory. Importantly, the effect of ketotifen in reducing tumor stiffness was further validated in sarcoma patients, highlighting its translational potential.

Our study suggests the targeting of MCs with clinically administered drugs, such as antihistamines, as a promising approach to overcome resistance to immunotherapy in sarcomas.

There are several modifiable factors that can be targeted to prevent and manage the occurrence and progression of cancer, and maintaining adequate exercise is a crucial one. Regular physical exercise has been shown to be a beneficial strategy in preventing cancer, potentially amplifying the effectiveness of established cancer therapies, alleviating certain cancer-related symptoms, and possibly mitigating side effects resulting from treatment. Nevertheless, the exact mechanisms by which exercise affects tumors, especially its impact on the tumor microenvironment (TME), remain uncertain. This review aims to present an overview of the beneficial effects of exercise in the context of cancer management, followed by a summary of the exercise parameters, especially exercise intensity, that need to be considered when prescribing exercise for cancer patients. Finally, we discuss the influence of exercise on the TME, including its effects on crucial immune cells (e.g., T cells, macrophages, neutrophils, natural killer cells, myeloid-derived suppressor cells, B cells), intratumor angiogenesis, and cancer metabolism. This comprehensive review provides up-to-date scientific evidence on the effects of exercise training on cancer and offers guidance to clinicians for the development of safe and feasible exercise training programs for cancer patients in clinical practice.