Hypoxia as a driver of resistance to immunotherapy

doi:10.1016/j.drup.2021.100787

Drug Resistance Updates

Volume 59, December 2021, 100787

https://doi.org/10.1016/j.drup.2021.100787 Get rights and content

Abstract

Hypoxia, a hallmark of solid tumors, determines the selection of invasive and aggressive malignant clones displaying resistance to radiotherapy, conventional chemotherapy or targeted therapy. The recent introduction of immunotherapy, based on immune checkpoint inhibitors (ICPIs) and chimeric antigen receptor (CAR) T-cells, has markedly transformed the prognosis in some tumors but also revealed the existence of intrinsic or acquired drug resistance. In the current review we highlight hypoxia as a culprit of immunotherapy failure. Indeed, multiple metabolic cross talks between tumor and stromal cells determine the prevalence of immunosuppressive populations within the hypoxic tumor microenvironment and confer upon tumor cells resistance to ICPIs and CAR T-cells. Notably, hypoxia-triggered angiogenesis causes immunosuppression, adding another piece to the puzzle of hypoxia-induced immunoresistance. If these factors concurrently contribute to the resistance to immunotherapy, they also unveil an unexpected Achille’s heel of hypoxic tumors, providing the basis for innovative combination therapies that may rescue the efficacy of ICPIs and CAR T-cells. Although these treatments reveal both a bright side and a dark side in terms of efficacy and safety in clinical trials, they represent the future solution to enhance the efficacy of immunotherapy against hypoxic and therapy-resistant solid tumors.

Section snippets

Introduction: the impact of hypoxia on tumors and response to therapy

Notwithstanding the compensatory neo-angiogenesis, hypoxic areas are a hallmark of rapidly growing tumors, because of the chaotic architecture of the neo-vessels, and the tendency to undergo vascular collapse under the pressure of growing tumor and stroma (Gacche and Assaraf, 2018; Huijbers et al., 2016; Kleibeuker et al., 2012; Nussenbaum and Herman, 2010). Hypoxic areas are heterogeneously distributed within the tumor bulk, because the continuous alternation between vessel formation and

The imprinting of hypoxia on tumor microenvironment reduces the efficacy of immune checkpoint inhibitors

Hypoxia may impair the efficacy of immunotherapy by acting at multiple levels. A hypoxic environment decreases the ratio between anti-tumor immune cells and immunotolerant or immunosuppressive cells. Furthermore, hypoxia directly increases the expression and activity of ICPs and ICP ligands (ICPLs) on immune-cells and tumor cells. The concurrent presence of immunosuppressive cells, anergic effector cells and immunoevasive cancer cells unequivocally reduces the efficacy of ICPIs.

Mitigating intratumor hypoxia to overcome resistance to immune checkpoint inhibitors: a versatile and open therapeutic field

The pharmacological strategies reducing the deleterious effects of hypoxia worked well in preclinical models to improve the efficacy of chemotherapy, radiotherapy and targeted therapies (Graham and Unger, 2018). Starting from these premises, inhibitors of HIF-1α, agents mitigating the effects of hypoxia, reoxygenation methods may work as immune-sensitizer agents as well. Different strategies have been tested.

Although pharmacological inhibitors of HIF are apparently the easiest category of drugs

The cross talk between hypoxia and angiogenesis: another piece of the puzzle determining the activity of immune checkpoint inhibitors

When the tumors grow, new blood vessels form to provide nutrients and O₂. However, the newly formed blood vessels are often structurally and morphologically aberrant, and create a TME with persistent or cycling hypoxia, acidosis and high interstitial fluid pressure (Lugano et al., 2020). These conditions impair the extravasation of immune cells and create an immunosuppressive landscape (Pietrobon and Marincola, 2021), but also offer new therapeutic opportunities to combine anti-angiogenic

Implication of hypoxia-driven changes in the efficacy of CAR T-cells

CAR T-cells represent an effective form of adoptive T-cell therapy (ATC), developed to circumvent the immunotolerance of the T-cell repertoire and the MHC restriction, and to direct specific cytotoxicity to a target molecule on malignant cells. In this approach, T-cells isolated from the patient (or from an allogeneic donor) are genetically modified to express a tailored CAR toward a specific tumor antigen. Then, they are expanded and infused into the patient. The first generation of CAR

Conclusions and future perspectives

Hypoxia is a driver of multiple aggressive features in tumors, inducing metabolic rewiring, apoptosis inhibition, cell migration and increased adaptability to unfavorable conditions. The first consequence of these transformations is the higher resistance of hypoxic tumors to chemotherapy and radiotherapy, as well as to other stressful conditions which usually kill normoxic cells including nutrient deprivation, calcium oscillation, endoplasmic reticulum stress (Akman et al., 2021; Belisario et

Funding

CR unit receives funding from the Italian Association of Cancer Research (AIRC; IG21408). ABSR unit is supported by Foundation for Science and Technology (FCT), Portugal (UID/NEU/04539/2019, UIDB/ 04539/2020 and UIDP/04539/2020). J.D.L.R. unit is funded by Fondo de Investigación Sanitaria—Instituto de Salud Carlos III (FIS—ISCIII, Ministry of Health of Spain; PI18/00591 and PT17/0009/0008) and by the FEDER European Union’s program. J.D.L.R. and C. R. are Vice-Chair and Chair of the COST-Action

Acknowledgements

This article is based upon work from COST Action CA17104 STRATAGEM, supported by COST (European Cooperation in Science and Technology) (www.cost.eu).

References (259)

S.A. Ackroyd et al.
Pembrolizumab and lenvatinib versus carboplatin and paclitaxel as first-line therapy for advanced or recurrent endometrial cancer: a Markov analysis
Gynecol. Oncol.
(2021)
A.C. Alves et al.
Biophysics in cancer: the relevance of drug-membrane interaction studies
Biochim. Biophys. Acta Biomembr.
(2016)
Y.G. Assaraf et al.
The multi-factorial nature of clinical multidrug resistance in cancer
Drug Resist. Updates
(2019)
E.E. Bram et al.
C421 allele-specific ABCG2 gene amplification confers resistance to the antitumor triazoloacridone C-1305 in human lung cancer cells
Biochem. Pharmacol.
(2007)
A. Brand et al.
LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells
Cell Metab.
(2016)
K.J. Briggs et al.
Paracrine induction of HIF by glutamate in breast cancer: EglN1 senses cysteine
Cell
(2016)
X. Cai et al.
Apatinib enhanced anti-PD-1 therapy for colon cancer in mice via promoting PD-L1 expression
Int. Immunopharmacol.
(2020)
X. Cao et al.
Towards the overcoming of anticancer drug resistance mediated by p53 mutations
Drug Resist. Updates
(2020)
C.H. Chang et al.
Metabolic competition in the tumor microenvironment is a driver of cancer progression
Cell
(2015)
T.C. Chen et al.
Associations among pretreatment tumor necrosis and the expression of HIF-1α and PD-L1 in advanced oral squamous cell carcinoma and the prognostic impact thereof
Oral Oncol.
(2015)

J. Chen et al.

Regulation of PD-L1: a novel role of pro-survival signalling in cancer

Ann. Oncol.

(2016)

M. Dal Bo et al.

New insights into the pharmacological, immunological, and CAR-T-cell approaches in the treatment of hepatocellular carcinoma

Drug Resist. Updates

(2020)

E.V. Dang et al.

Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1

Cell

(2011)

Y. Diesendruck et al.

Novel immune check point inhibiting antibodies in cancer therapy-Opportunities and challenges

Drug Resist. Updates

(2017)

J. Dong et al.

Medicinal chemistry strategies to discover P-glycoprotein inhibitors: an update

Drug Resist. Updates

(2020)

R. Du et al.

HIF1α induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion

Cancer Cell

(2008)

A. Elorza et al.

HIF2α acts as an mTORC1 activator through the amino acid carrier SLC7A5

Mol. Cell

(2012)

H.K. Eltzschig et al.

Central role of Sp1-regulated CD39 in hypoxia/ischemia protection

Blood

(2009)

N. Erin et al.

Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance

Drug Resist. Updat.

(2020)

K. Fischer et al.

Inhibitory effect of tumor cell-derived lactic acid on human T cells

Blood

(2007)

R.N. Gacche et al.

Redundant angiogenic signaling and tumor drug resistance

Drug Resist. Updates

(2018)

A. Giatromanolaki et al.

Ectonucleotidase CD73 and CD39 expression in non-small cell lung cancer relates to hypoxia and immunosuppressive pathways

Life Sci.

(2020)

E. Hays et al.

YY1 regulates cancer cell immune resistance by modulating PD-L1 expression

Drug Resist. Updat.

(2019)

E.J. Huijbers et al.

Role of the tumor stroma in resistance to anti-angiogenic therapy

Drug Resist. Updates

(2016)

N.A. Hussein et al.

The role of endolysosomal trafficking in anticancer drug resistance

Drug Resist. Updates

(2021)

Y. Jiang et al.

Communication between EMT and PD-L1 signaling: new insights into tumor immune evasion

Cancer Lett.

(2020)

J.V. Joseph et al.

Hypoxia enhances migration and invasion in glioblastoma by promoting a mesenchymal shift mediated by the HIF1α – ZEB1 axis

Cancer Lett.

(2015)

W.G. Kaelin et al.

Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway

Mol. Cell

(2008)

R.J. Kathawala et al.

The modulation of ABC transporter-mediated multidrug resistance in cancer: a review of the past decade

Drug Resist. Updates

(2015)

A. Kawazoe et al.

Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial

Lancet Oncol.

(2020)

E.A. Kleibeuker et al.

Combining angiogenesis inhibition and radiotherapy: a double-edged sword

Drug Resist. Updates

(2012)

J.N. Kochenderfer et al.

Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19

Blood

(2010)

E. Kon et al.

Immune checkpoint inhibitor combinations: current efforts and important aspects for success

Drug Resist. Updates

(2019)

V.B. Abdul-Salam et al.

CLIC4/Arf6 pathway: a new lead in BMPRII inhibition in pulmonary hypertension

Circ. Res.

(2019)

M. Ai et al.

Tumor hypoxia drives immune suppression and immunotherapy resistance

J. Immunother. Cancer

(2015)

M. Akman et al.

Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons

J. Exp. Clin. Cancer Res.

(2021)

E. Allen et al.

Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation

Sci. Transl. Med.

(2017)

F. Antonangeli et al.

Regulation of PD-L1 expression by NF-κB in cancer

Front. Immunol.

(2020)

A.B. Apolo et al.

Phase I study of cabozantinib and nivolumab alone or with ipilimumab for advanced or metastatic urothelial carcinoma and other genitourinary tumors

J. Clin. Oncol.

(2020)

A.M. Arance et al.

Lenvatinib (len) plus pembrolizumab (pembro) for patients (pts) with advanced melanoma and confirmed progression on a PD-1 or PD-L1 inhibitor: updated findings of LEAP-004

J. Clin. Oncol.

(2021)

M.B. Atkins et al.

Patient-reported outcomes from the phase 3 randomized IMmotion151 trial: atezolizumab + bevacizumab vs sunitinib in treatment-naive metastatic renal cell carcinoma

Clin. Cancer Res.

(2020)

M. Balsamo et al.

Hypoxia downregulates the expression of activating receptors involved in NK-cell-mediated target cell killing without affecting ADCC

Eur. J. Immunol.

(2013)

T.M. Bauer et al.

The oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC): updated follow-up of a phase I/II study

J. Clin. Oncol.

(2021)

D.C. Belisario et al.

Hypoxia dictates metabolic rewiring of tumors: implications for chemoresistance

Cells

(2020)

R. Berahovich et al.

Hypoxia selectively impairs CAR-T cells in vitro

Cancers (Basel)

(2019)

A. Bex et al.

A Phase II, single-arm trial of neoadjuvant axitinib plus avelumab in patients with localized renal cell carcinoma who are at high risk of relapse after nephrectomy (NEOAVAX)

Future Oncol.

(2019)

E. Boedtkjer

Na(+),HCO(3)(-) cotransporter NBCn1 accelerates breast carcinogenesis

Cancer Metastasis Rev.

(2019)

E. Bram et al.

Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates

Cancer Chemother. Pharmacol.

(2006)

M.L. Burr et al.

CMTM6 maintains the expression of PD-L1 and regulates anti-Tumour immunity

Nature

(2017)

Q. Cai et al.

Potential strategies against resistance to CAR T-cell therapy in haematological malignancies

Ther. Adv. Med. Oncol.

(2020)

Cited by (95)

MRI-guided dynamic risk assessment in cervical cancer based on tumor hypoxia at diagnosis and volume response at brachytherapy
2024, Radiotherapy and Oncology
Improvements in treatment outcome for patients with locally advanced cervical cancer (LACC) require a better classification of patients according to their risk of recurrence. We investigated whether an imaging-based approach, combining pretreatment hypoxia and tumor response during therapy, could improve risk classification.
Ninety-three LACC patients with T2-weigthed (T2W)-, dynamic contrast enhanced (DCE)- and diffusion weighted (DW)-magnetic resonance (MR) images acquired before treatment, and T2W- and, for 64 patients, DW-MR images, acquired at brachytherapy, were collected. Pretreatment hypoxic fraction (HF_pre) was determined from DCE- and DW-MR images using the consumption and supply-based hypoxia (CSH)-imaging method. Volume regression at brachytherapy was assessed from T2W-MR images and combined with HF_pre. In 17 patients with adequate DW-MR images at brachytherapy, the apparent diffusion coefficient (ADC), reflecting tumor cell density, was calculated. Change in ADC during therapy was combined with volume regression yielding functional regression as explorative response measure. Endpoint was disease free survival (DFS).
HF_pre was the strongest predictor of DFS, but a significant correlation with outcome was found also for volume regression. The combination of HF_pre and volume regression showed a stronger association with DFS than HF_pre alone. Patients with disease recurrence were selected to either the intermediate- or high-risk group with a 100 % accuracy. Functional regression showed a stronger correlation to HF_pre than volume regression.
The combination of pretreatment hypoxia and volume regression at brachytherapy improved patient risk classification. Integration of ADC with volume regression showed promise as a new tumor response parameter.
Identification of a novel cancer-associated fibroblasts gene signature based on bioinformatics analysis to predict prognosis and therapeutic responses in breast cancer
2024, Heliyon
Cancer-associated fibroblasts (CAFs) provide suitable conditions for growth of tumor cell and facilitate tumor progression. Hence, we aimed to identify a CAFs-related gene signature associated with the prognosis of patients with breast cancer (BRCA). We downloaded datasets from Gene Expression Omnibus (GEO) and confirmed the correlation between CAFs infiltration scores and prognosis. By performing weighted gene co-expression network analysis (WGCNA) and Lasso Cox regression analysis, we constructed a four-gene (COL5A3, FN1, POSTN, and RARRES2) prognostic CAFs signature model. Based on the median risk score of CAFs, patients with BRCA were divided into high- and low-risk groups. Compared with low-risk group, patients in high-risk group exhibited a poor prognosis and limited response to immunotherapy. Furthermore, patients with high CAFs risk scores were found to have a detrimental prognosis due to the induction of immunosuppressive cell infiltration, resulting in an immunosuppressive tumor microenvironment. Importantly, we found that CAFs overexpressing FN1 and POSTN significantly promoted the wound healing and invasion ability of tumor cells in vitro validation. Taking together, we identified a four-gene prognostic CAFs signature, which was proven to be a reliable indicator for prognosis and therapeutic efficacy in patients with BRCA. This study provided evidence for novel CAFs-based stromal therapy.
Nanocarriers address intracellular barriers for efficient drug delivery, overcoming drug resistance, subcellular targeting and controlled release
2024, Advanced Drug Delivery Reviews
The cellular barriers are major bottlenecks for bioactive compounds entering into cells to accomplish their biological functions, which limits their biomedical applications. Nanocarriers have demonstrated high potential and benefits for encapsulating bioactive compounds and efficiently delivering them into target cells by overcoming a cascade of intracellular barriers to achieve desirable therapeutic and diagnostic effects. In this review, we introduce the cellular barriers ahead of drug delivery and nanocarriers, as well as summarize recent advances and strategies of nanocarriers for increasing internalization with cells, promoting intracellular trafficking, overcoming drug resistance, targeting subcellular locations and controlled drug release. Lastly, the future perspectives of nanocarriers for intracellular drug delivery are discussed, which mainly focus on potential challenges and future directions. Our review presents an overview of intracellular drug delivery by nanocarriers, which may encourage the future development of nanocarriers for efficient and precision drug delivery into a wide range of cells and subcellular targets.
Enhancing photodynamic immunotherapy by reprograming the immunosuppressive tumor microenvironment with hypoxia relief
2024, Journal of Controlled Release
Tumor hypoxia impairs the generation of reactive oxygen species and the induction of immunogenic cell death (ICD) for photodynamic therapy (PDT), thus impeding its efficacy and the subsequent immunotherapy. In addition, hypoxia plays a critical role in forming immunosuppressive tumor microenvironments (TME) by regulating the infiltration of immunosuppressive tumor-associated macrophages (TAMs) and the expression of programmed death ligand 1 (PD-L1). To simultaneously tackle these issues, a MnO₂-containing albumin nanoplatform co-delivering IR780, NLG919, and a paclitaxel (PTX) dimer is designed to boost photodynamic immunotherapy. The MnO₂-catalyzed oxygen supply bolsters the efficacy of PDT and PTX-mediated chemotherapy, collectively amplifying the induction of ICD and the expansion of tumor-specific cytotoxic T lymphocytes (CTLs). More importantly, hypoxia releif reshapes the immunosuppressive TME via down-regulating the intratumoral infiltration of M2-type TAMs and the PD-L1 expression of tumor cells to enhance the infiltration and efficacy of CTLs in combination with immune checkpoint blockade (ICB) by NLG919, consequently eradicating primary tumors and almost completely preventing tumor relapse and metastasis. This study sets an example of enhanced immunotherapy for breast cancers through dual ICD induction and simultaneous immunosuppression modulation via both hypoxia relief and ICB, providing a strategy for the treatment of other hypoxic and immunosuppressive cancers.
Current advances in modulating tumor hypoxia for enhanced therapeutic efficacy
2024, Acta Biomaterialia
Hypoxia is a common feature of most solid tumors, which promotes the proliferation, invasion, metastasis, and therapeutic resistance of tumors. Researchers have been developing advanced strategies and nanoplatforms to modulate tumor hypoxia to enhance therapeutic effects. A timely review of this rapidly developing research topic is therefore highly desirable. For this purpose, this review first introduces the impact of hypoxia on tumor development and therapeutic resistance in detail. Current developments in the construction of various nanoplatforms to enhance tumor treatment in response to hypoxia are also systematically summarized, including hypoxia-overcoming, hypoxia-exploiting, and hypoxia-disregarding strategies. We provide a detailed discussion of the rationale and research progress of these strategies. Through a review of current trends, it is hoped that this comprehensive overview can provide new prospects for clinical application in tumor treatment.
As a common feature of most solid tumors, hypoxia significantly promotes tumor progression. Advanced nanoplatforms have been developed to modulate tumor hypoxia to enhanced therapeutic effects. In this review, we first introduce the impact of hypoxia on tumor progression. Current developments in the construction of various nanoplatforms to enhance tumor treatment in response to hypoxia are systematically summarized, including hypoxia-overcoming, hypoxia-exploiting, and hypoxia-disregarding strategies. We discuss the rationale and research progress of the above strategies in detail, and finally introduce future challenges for treatment of hypoxic tumors. By reviewing the current trends, this comprehensive overview can provide new prospects for clinical translatable tumor therapy.
High expression of B7-H3 on monocyte/macrophages in tumor microenvironment promotes lung cancer progression by inhibiting apoptosis
2024, Translational Oncology
Monocyte/macrophages constitute a significant population of tumor-infiltrating immune cells and play a crucial role in tumor growth, invasion, and metastasis. B7-H3, has immune regulatory functions, however, it is unclear whether B7-H3 expressed on monocyte/macrophages plays a significance role in tumor progression. We found B7-H3 was high-expressed on monocyte/macrophages in tumor microenvironment compared with adjacent tissues in lung cancer, and its expression level was positively correlated with the number of monocyte/macrophages. Furthermore, the expression of B7-H3 was related to clinical stage and lymph node metastasis. Moreover, miR-29a-3p negatively regulated B7-H3, and the expression of B7-H3 on THP-1-derived macrophages was regulated by secreting exosomes containing miR-29a-3p. In addition, knockdown of B7-H3 promoted macrophage apoptosis under hypoxia. Mechanistically, B7-H3 enhanced the antiapoptotic ability of macrophage by up-regulating HIF-1ɑ via activating NF-κB. Taken together, these results imply that B7-H3 as a therapeutic target could hold promise for enhancing anti-tumor immune responses in individuals diagnosed with lung cancer.

View all citing articles on Scopus

¹: Equal contribution.

View full text

Hypoxia as a driver of resistance to immunotherapy

Abstract

Section snippets

Introduction: the impact of hypoxia on tumors and response to therapy

The imprinting of hypoxia on tumor microenvironment reduces the efficacy of immune checkpoint inhibitors

Mitigating intratumor hypoxia to overcome resistance to immune checkpoint inhibitors: a versatile and open therapeutic field

The cross talk between hypoxia and angiogenesis: another piece of the puzzle determining the activity of immune checkpoint inhibitors

Implication of hypoxia-driven changes in the efficacy of CAR T-cells

Conclusions and future perspectives

Funding

Acknowledgements

Gynecol. Oncol.

Biochim. Biophys. Acta Biomembr.

Drug Resist. Updates

Biochem. Pharmacol.

Cell Metab.

Cell

Int. Immunopharmacol.

Drug Resist. Updates

Cell

Oral Oncol.

Ann. Oncol.

Drug Resist. Updates

Cell

Drug Resist. Updates

Drug Resist. Updates

Cancer Cell

Mol. Cell

Blood

Drug Resist. Updat.

Blood

Drug Resist. Updates

Life Sci.

Drug Resist. Updat.

Drug Resist. Updates

Drug Resist. Updates

Cancer Lett.

Cancer Lett.

Mol. Cell

Drug Resist. Updates

Lancet Oncol.

Drug Resist. Updates

Blood

Drug Resist. Updates

CLIC4/Arf6 pathway: a new lead in BMPRII inhibition in pulmonary hypertension

Circ. Res.

Tumor hypoxia drives immune suppression and immunotherapy resistance

J. Immunother. Cancer

Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons

J. Exp. Clin. Cancer Res.

Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation

Sci. Transl. Med.

Regulation of PD-L1 expression by NF-κB in cancer

Front. Immunol.

Phase I study of cabozantinib and nivolumab alone or with ipilimumab for advanced or metastatic urothelial carcinoma and other genitourinary tumors

J. Clin. Oncol.

Lenvatinib (len) plus pembrolizumab (pembro) for patients (pts) with advanced melanoma and confirmed progression on a PD-1 or PD-L1 inhibitor: updated findings of LEAP-004

J. Clin. Oncol.

Patient-reported outcomes from the phase 3 randomized IMmotion151 trial: atezolizumab + bevacizumab vs sunitinib in treatment-naive metastatic renal cell carcinoma

Clin. Cancer Res.

Hypoxia downregulates the expression of activating receptors involved in NK-cell-mediated target cell killing without affecting ADCC

Eur. J. Immunol.

The oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC): updated follow-up of a phase I/II study

J. Clin. Oncol.

Hypoxia dictates metabolic rewiring of tumors: implications for chemoresistance

Cells

Hypoxia selectively impairs CAR-T cells in vitro

Cancers (Basel)

A Phase II, single-arm trial of neoadjuvant axitinib plus avelumab in patients with localized renal cell carcinoma who are at high risk of relapse after nephrectomy (NEOAVAX)

Future Oncol.

Na(+),HCO(3)(-) cotransporter NBCn1 accelerates breast carcinogenesis

Cancer Metastasis Rev.

Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates

Cancer Chemother. Pharmacol.

CMTM6 maintains the expression of PD-L1 and regulates anti-Tumour immunity

Nature

Potential strategies against resistance to CAR T-cell therapy in haematological malignancies

Ther. Adv. Med. Oncol.