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Northeastern University · Chemical and Biomolecular Engineering
Active 1976–2026
Stephen Hatfield is an Assistant Professor in the Department of Pharmaceutical Sciences at Northeastern University College of Engineering. He holds a PhD in Biology from Northeastern University, earned in 2012. His research focuses on biomolecular and biomedical areas, contributing to the understanding of biological processes at the molecular level. As an affiliated faculty member in the Chemical Engineering department, he is involved in advancing research in his field and mentoring students, including those recognized for their undergraduate research efforts. His work is part of Northeastern's broader commitment to research excellence and experiential learning in engineering and biomedical sciences.
bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-21
Therapeutic cancer vaccines represent a promising approach to boost patients' own immune system to fight cancer. However, many vaccine candidates have shown limited success in clinical trials in large part due to the insufficient antigen delivery to overcome tolerance and hypoxia mediated immunosuppressive mechanisms. Cryogel-based delivery scaffolds have emerged as a promising platform for cancer vaccines due to their biocompatibility and macroporous structure that allows for effective delivery to infiltrating antigen-presenting cells. However, these systems are limited by rapid, diffusion-mediated burst release of encapsulated recombinant proteins and local hypoxia-driven immunosuppression within the scaffold. Herein, we demonstrate that click conjugation of a tumor-associated protein within cryogel-based vaccines, combined with our new O 2 -generating platform (Click O 2 -Cryogel VAX ), helps overcome immune suppression and weak antigenicity and primes effective anti-cancer immune responses. Sustained antigen delivery promotes cellular memory and Th1-mediated anti-cancer responses. By reversing hypoxia-driven immunosuppression, O 2 acts as a powerful co-adjuvant to enhance humoral immunity. Together, Click O 2 -Cryogel VAX supports a robust antitumor response that inhibits tumor growth and prolongs survival in a therapeutic prostate cancer model. These findings support the further research and development of Click O 2 -Cryogel VAX as an effective delivery platform for therapeutic cancer vaccines.
Bioengineered cryogels overcome hypoxia-driven tolerance and restore antitumor immunity
Cell Biomaterials · 2026-03-01
International audience
bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-29
Compact RNA-guided nucleases with favorable targeting properties are challenging to discover due to their low natural abundance. Here, we develop a structure-led search strategy -leveraging predicted protein folds and sequence-independent similarity metrics -to systematically identify extremely low-homology compact RNA-guided nucleases across vast metagenomic datasets with high computational efficiency. Homology clustering resolved these proteins into distinct groups, for which we performed comprehensive PAM profiling and evaluated editing efficiency in eukaryotic cells. This structure-guided discovery revealed a previously undiscovered landscape of compact nuclease subtypes that exhibit extensive protospacer-adjacent motif (PAM) diversity, expanding the targeting potential of compact editors. Comparative analysis across the novel RNA-guided nuclease families demonstrates that compact systems are not intrinsically limited to highly constrained PAMs but instead have a broad and previously unknown breadth of genome targeting capabilities, comparable to that of Cas9 and far exceeding common transposon-derived systems. Additionally, this search revealed that a compact transposon-associated motif (TAM) is a prerequisite for the emergence of a CRISPR-Cas system from ancestral transposons, before protein domain expansions increase the target length and specificity constraints. These results enrich the catalog of RNA-guided nuclease architectures and contribute validated compact genome editing tools with broad and diverse PAM recognition, which may have therapeutic applications.
Polymer oxidation: A strategy for the controlled degradation of injectable cryogels
Materials Today Bio · 2025-04-08 · 6 citations
GM cryogels accelerates ovalbumin release and enhances its uptake and response by immune cells in mice. This versatile oxidation strategy can be applied to a wide range of polymers, allowing better control over cryogel degradation, and advancing their potential for biomedical applications and clinical translation.
Breaking barriers: Smart vaccine platforms for cancer immunomodulation
Cancer Communications · 2025-02-03 · 8 citations
Despite significant advancements in cancer treatment, current therapies often fail to completely eradicate malignant cells. This shortfall underscores the urgent need to explore alternative approaches such as cancer vaccines. Leveraging the immune system's natural ability to target and kill cancer cells holds great therapeutic potential. However, the development of cancer vaccines is hindered by several challenges, including low stability, inadequate immune response activation, and the immunosuppressive tumor microenvironment, which limit their efficacy. Recent progress in various fields, such as click chemistry, nanotechnology, exosome engineering, and neoantigen design, offer innovative solutions to these challenges. These achievements have led to the emergence of smart vaccine platforms (SVPs), which integrate protective carriers for messenger ribonucleic acid (mRNA) with functionalization strategies to optimize targeted delivery. Click chemistry further enhances SVP performance by improving the encapsulation of mRNA antigens and facilitating their precise delivery to target cells. This review highlights the latest developments in SVP technologies for cancer therapy, exploring both their opportunities and challenges in advancing these transformative approaches.
JCI Insight · 2025-03-23 · 16 citations
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.
The Journal of Immunology · 2025-11-01
Abstract Description Chimeric Antigen Receptor (CAR) T cells have induced remarkable clinical responses in patients with hematological cancers. However, CAR-T therapies against solid tumors have not elicited similar outcomes because immunosuppressive barriers in the tumor microenvironment (TME) effectively attenuate anti-tumor activity. Here, we developed a multifaceted approach to engineer allogeneic (‘off-the-shelf’) CAR-T cells resistant to both biochemical (hypoxia-adenosinergic) and immunological (PD-L1 and TGF-β) inhibitory signaling using an adenine base editor and a CRISPR-Cas12b nuclease. The resulting CAR-T product comprised a combination of six gene edits to evade allorejection (B2M, CIITA), prevent graft-versus-host disease (CD3E) and resist biochemical (ADORA2A) and immunological (PDCD1, TGFBR2) negative regulation. This novel combinatorial genetic disruption in CAR-T cells enabled anti-tumor efficacy leading to improved tumor elimination and survival in humanized mouse models recapitulating a human TME. Our unique strategy conferred CAR-T cells resistance to a diverse TME and may unlock the therapeutic potential of CAR-T cells against solid tumors. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
Nature Communications · 2025-11-23 · 1 citations
Chimeric Antigen Receptor (CAR) T cells have induced remarkable clinical responses in patients with hematological cancers. However, CAR T-cell therapies against solid tumors have not elicited similar outcomes since immunosuppressive barriers in the tumor microenvironment attenuate anti-tumor activity. Here, we describe a multifaceted approach to engineer allogeneic CAR T-cells resistant to both biochemical (hypoxia-adenosinergic) and immunological (PD-L1 and TGF-β) inhibitory signaling using an adenine base editor and a CRISPR-Cas12b nuclease. The resulting EGFR-targeting CAR T-cell product comprised a combination of six gene edits designed to evade allorejection (B2M, CIITA), prevent graft-versus-host disease (CD3E) and overcome biochemical (ADORA2A) and immunological (PDCD1, TGFBR2) barriers in solid tumor microenvironment of subcutaneously grown EGFR+ human lung tumor xenografts. This combinatorial genetic disruption enhances CAR T cell effector function and anti-tumor efficacy leading to improved tumor elimination and survival in xenograft and humanized mouse solid tumor models. Our strategy confers CAR T cells resistance to multiple clinically relevant inhibitory signaling pathways that are amplified in hypoxic tumor areas and may improve the therapeutic potential of CAR T-cells against solid tumors. Resistance signaling in the tumor microenvironment limits CAR T cell therapy in solid tumors. This study introduces a multiplex engineered CAR T cell strategy using six gene edits to overcome multiple inhibitory barriers.
bioRxiv (Cold Spring Harbor Laboratory) · 2024-02-21
Abstract Hypoxia-HIF-1α-driven immunosuppressive transcription and cAMP-elevating signaling through A2A-adenosine receptors (A2AR) 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 patient’s refractory to all other therapies have confirmed the importance of targeting hypoxia-adenosinergic signaling. We report a novel and feasible approach to target the upstream stage of hypoxia-adenosinergic immunosuppression using an oxygen-carrying nanoemulsion (perfluorocarbon blood substitute). It is shown that oxygenation agent therapy i) eliminates tumor hypoxia, ii) improves efficacy of endogenously developed and adoptively transferred T cells, and thereby iii) 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 re-programming 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 immune-suppressive to immune-permissive prior to adoptive cell therapy, or other forms of immunotherapy. Summary Oxygen delivering nanoemulsions and respiratory hyperoxia address limitations of blood vessel-mediated tumor oxygenation and promote anti-tumor immune responses to enhance immunotherapy.
bioRxiv (Cold Spring Harbor Laboratory) · 2023-08-04 · 2 citations
Abstract Biochemical and immunological negative regulators converge to inhibit tumor-reactive Chimeric Antigen Receptor T (CAR-T) cells, which may explain clinical failures of CAR-T cell therapies against solid tumors. Here, we developed a multifaceted approach to genetically engineer allogeneic (‘off -the-shelf’) CAR-T cells resistant to both biochemical (adenosine) and immunological (PD-L1 and TGF-β) inhibitory signaling. We multiplexed an adenine base editor with a CRISPR-Cas12b nuclease to manufacture a CAR-T cell product comprising six gene edits to evade allorejection ( B2M, CIITA ), prevent graft-versus-host disease ( CD3E ) and resist major biochemical ( ADORA2A ) and immunological ( PDCD1 , TGFBR2 ) immunosuppressive barriers in solid tumors. Combinatorial genetic disruption in CAR-T cells enabled superior anti-tumor efficacy leading to improved tumor elimination and survival in humanized mouse models that recapitulated the suppressive features of a human tumor microenvironment (TME). This novel engineering strategy conferred CAR-T cells resistance to a diverse TME, which may unlock the therapeutic potential of CAR-T cells against solid tumors. One Sentence Summary Multiplex genome engineered CAR-T cells resistant to allorejection and the convergence of biochemical and immunological negative regulators within the tumor microenvironment exhibit superior efficacy against solid tumors.
Michail V. Sitkovsky
Northeastern University
Bryan Belikoff
Mallinckrodt (United States)
Daniel G. Remick
Boston University
Jon A. Buras
Northeastern University
Chang Hc
Chung Shan Medical University Hospital
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Grant R. Kolar
Saint Louis University
Ching‐Hsiung Lin
Changhua Christian Hospital
Shu‐Lang Liao
National Yang Ming Chiao Tung University