The Tumor Microenvironment in NSCLC: A Hidden Force Shaping Cancer Growth and Treatment Response

When we talk about non-small cell lung cancer (NSCLC), most people think of tumor cells as the main problem. But in reality, cancer cells are just one part of a larger, highly organized ecosystem: the tumor microenvironment (TME). This microenvironment is made up of structural cells, immune cells, signaling molecules, and even chemical fluctuations like acidity and oxygen levels. Together, these factors determine how tumors grow, spread, and respond to treatment[1].

Recent spatial biology studies have shown that NSCLC tumors contain two broad types of “neighborhoods”. Some areas are rich in immune cells actively fighting the tumor. Others are dominated by stromal and suppressive cells that keep immune cells out, allowing the cancer to thrive. Understanding which are the key players in this environment can reveal why some tumors respond well to therapy while others resist it[2].

Cancer-Associated Fibroblasts: The Tumor’s Structural Architects

One of the most influential cell types in the NSCLC microenvironment is the cancer-associated fibroblast, or CAF. These cells provide structure to the tumor, but they also shape how it behaves. Unlike normal fibroblasts, CAFs secrete signaling molecules such as TGF-B, CXCL12, and VCAM-1, which stiffen the tissue around the tumor, making it harder for immune cells to enter[1].

CAFs don’t come from a single source. They can arise from normal fibroblasts, bone marrow-derived stem cells, epithelial cells, or even from immune cells that change identity under certain signals[1].

CAFS are also a major driver of treatment resistance. They can trigger epithelial-mesenchymal transition (EMT), making cancer cells more invasive and resistant to drugs. Through pathways like YAP/TAZ and the secretion of growth factors such as HGF and IGF1, CAFs reduce the effectiveness of chemotherapy and targeted therapies[1].

Tumor-associated macrophages, or TAMs, are another abundant cell population in NSCLC. These immune cells can either attack tumors or support them, depending on their state. Some TAMs are pro-inflammatory and help T cells infiltrate the tumor. Others adopt a suppressive, “M2-like” role, releasing molecules like IL-10 and TGF-β that weaken immune responses, promote new blood vessel formation, and help tumors spread[2].

Importantly, TAMs and CAFs work closely together. Through chemical signaling loops, they reinforce each other’s suppressive effects. Their collaboration builds physical and immunological barriers that keep killer T cells from reaching tumor cells[2].

Myeloid-Derived Suppressor Cells: Silencing the Immune System

Another key player is the myeloid-derived suppressor cell (MDSC). These cells come in monocytic and granulocytic forms, and their main role in the TME is to shut down the immune attack. They block T-cell proliferation, encourage the expansion of regulatory T cells (which suppress immunity), and release TGF-β and IL-10 to maintain a tolerant, tumor-friendly environment. High levels of MDSCs in the blood are associated with poorer outcomes and lower response rates to immunotherapy.

T Cells: The Immune Frontline

T cells are at the center of the body’s ability to recognize and kill cancer cells. In NSCLC, the spatial distribution of T cells matters. In “immune-rich” zones, cytotoxic CD8 T cells and helper T cells coordinate strong antitumor responses. High numbers of these cells are linked to better survival and better responses to PD-1/PD-L1 checkpoint inhibitors[1].

However, in fibrotic, acidic, or hypoxic areas of the tumor, T cells become exhausted. After prolonged exposure to cancer antigens and suppressive signals, they start expressing molecules like PD-1 and TIM-3, losing their ability to attack. Regulatory T cells (Tregs) further suppress activity by secreting IL-10 and IL-35. Some tumors also contain special immune structures called tertiary lymphoid structures, which are associated with stronger responses to immunotherapy[1].

The Crosstalk

These different cell types don’t act alone. CAFs and TAMs co-regulate fibrosis and suppression through shared hypoxia-driven pathways. MDSCs are recruited by CAFs and contribute to immune silencing. T cells are excluded or exhausted in these fibrotic zones. Hypoxia caused by the dense matrix activates more TGF-β and HIF1a, feeding into the same cycle.

The result is a self-sustaining feedback loop that protects the tumor from both the immune system and therapies. This is one reason why standard treatments can lose effectiveness, particularly in advanced disease.

Targeting Tumor Acidity with L-DOS47

One of the defining features of this hostile microenvironment is its acidity. The extracellular pH in tumor regions can drop below 6.8, compared to the normal physiological pH of around 7.4. Acidic conditions favor tumor invasion, encourage immune suppression, and reduce the potency of therapies. L-DOS47 is an investigational therapy designed to tackle this specific problem. It combines an antibody fragment that targets CEACAM6-a protein commonly found on NSCLC cells with the enzyme urease. Once bound to the tumor, the enzyme converts naturally occurring urea into ammonia and carbon dioxide, locally raising the pH.

By normalizing acidity, L-DOS47 helps restore T-cell function, shifts macrophages toward a more inflammatory state, and disrupts the physical and chemical barriers that tumors use to protect themselves. Early clinical trials in NSCLC have shown that this approach is well tolerated and may enhance the effectiveness of chemotherapy.

A New Way of Thinking About Treatment

The NSCLC tumor microenvironment is not just background tissue. It is an active, evolving network that shapes how tumors grow, spread, and respond to treatment. CAFs create barriers; TAMs and MDSCs suppress immunity; T cells fight back but are often exhausted; acidic and hypoxic conditions raise the barriers to anti-cancer immunity and therapies, making cancers harder-to-treat.

Targeting the metabolic environment, such as through pH modulation with L-DOS47, represents a promising new strategy. By changing the ecosystem rather than just attacking tumor cells, we may be able to turn immunologically “cold,” resistant tumors into more vulnerable ones and improve outcomes for patients with NSCLC.

Ref:

1. Rahal Z, El Darzi R, Moghaddam SJ, Cascone T, Kadara H. Tumour and microenvironment crosstalk in NSCLC progression and response to therapy. Nat Rev Clin Oncol. 2025 Jul;22(7):463-482. doi: 10.1038/s41571-025-01021-1. Epub 2025 May 16. PMID: 40379986; PMCID: PMC12227073.

2. Katarína BalážováHans CleversAntonella FM Dost (2023) The role of macrophages in non-small cell lung cancer and advancements in 3D co-cultures eLife 12:e82998. https://doi.org/10.7554/eLife.82998

Jacek Antas

Chief Executive Officer

Jacek Antas is a shareholder of the Company, has spent more than 25 years in the financial services industry holding various positions in sales and consulting.

Mr. Antas obtained a master’s degree from the Warsaw School of Economics and has served as a board member of various
companies throughout his career.

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James B. Murphy

Chief Financial Officer

Mr. Murphy is a certified public accountant with over thirty years of experience in finance and operations management. He is currently a consultant with Danforth Advisors LLC (“Danforth”), a leading provider of outsourced strategic and operational specialists across functions in the life sciences industry. While at Danforth, Mr. Murphy has served over fifteen private and publicly held life sciences companies as CFO and CFO Advisor, helping them secure over USD 0.5 billion in financing and successfully execute pivotal asset transactions. Mr. Murphy functions as a consultant to Helix pursuant to a consulting agreement between the Company and Danforth.

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Thomas Mehrling

Medical Adviser

Thomas Mehrling (PhD in Pharmacology and MD) has over 20 years’ experience in multinational Pharma companies developing novel oncology compounds from preclinical research through to registration. Prior to entering the industry, he spent 13 years as an MD at the University Hospital in Frankfurt, working on preclinical and translational projects. He served as Director of European Oncology at Mundipharma International (2003–2013), building the company’s first European oncology business from the ground up out of Cambridge, UK, and completing the clinical development, registration and launch of two major products in Europe, DepoCyte® and Levact® (Ribomustin® and Treanda®). In 2013, he led the establishment of the Mundipharma Group’s start-up, Mundipharma EDO, developing anti-cancer therapeutics for solid tumours out of Basel, Switzerland.

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Kim Gaspar

Director Quality Assurance

Kim is the Director of Quality Assurance at Helix BioPharma Corp. An experienced quality assurance professional with expertise in Canadian, US, and EU regulations, she has been involved in all aspects of Phase I/II biopharmaceutical product development over the years, including regulatory submissions, QC laboratory compliance, tech transfer and third-party oversight of CMC activities, clinical QA, and bioanalytical data analysis. Kim joined Helix in 2000, transitioning into QA in 2003. She holds a B.Sc in Biochemistry and a Ph.D in Veterinary Physiological Sciences, both from the University of Saskatchewan.

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Brenda Lee

Director Clinical Operations

Brenda is the Clinical Operations Director at Helix Biopharma Corp. A clinical research operations professional with 25 years of experience managing clinical trials, ranging from early Phase I to late Phase IIIb/IV studies, she brings experience in clinical study protocol writing and development, trial start-up and vendor management, and a proven track record in planning and managing clinical trials to quality standards, timelines and budget. Brenda joined Helix Biopharma Corp. in 2018, working to advance the clinical program of L-DOS47. She holds B.Sc and M.Sc. degrees from the University of Toronto, specializing in Nutritional Sciences and Human Biology.

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Jerzy Leszczynski

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Janusz Grabski

Director, Chair of Audit Committee

Janusz (John) Grabski is a lawyer specialized in corporate and real estate law with over twenty years of experience.

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Malgorzata Laube

Director

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Jacek Antas

Chairman of the Board

Jacek Antas is a shareholder of the Company, has spent more than 25 years in the financial services industry holding various positions in sales and consulting.

Mr. Antas obtained a master’s degree from the Warsaw School of Economics and has served as a board member of various
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Jonathan Davis

Advisor, ADC Discovery

Jonathan Davis received his Ph.D. from University of California, San Francisco, where he studied protein structure and function using NMR. After a post-doc at Harvard Medical School exploring RNA selection and structure in the labs of Jack Szostak and Gerhard Wagner, he went to work at EMD Serono, where his work involved improving antibody-based therapeutics, inventing a platform technology for generating heterodimeric Fcs as a basis for multifunctional molecules, and developing a novel scaffold based on an artificially-designed protein from David Baker’s lab. In 2008 he took a job at Bristol-Myers Squibb in Waltham/Cambridge MA, working on antibody discovery and platform development in a wide range of therapeutic areas, with a particular focus on multispecific therapeutics. He moved to Madison, WI in 2019 to take on the role of VP of Innovation and Strategy at Invenra, a biotech focused on bispecific antibodies, and where he is currently head of the Scientific Advisory Board. In early 2024 he left the corporate world to found Creative Antibodies, a consulting firm that helps guide companies to successful antibody discovery and development projects, from mAbs to multispecifics, ADCs, and other formats. Outside of science, Jonathan is a conservatory trained cellist, plays numerous other instruments, and founded the UCSF Orchestra (now Symphony Parnassus) in San Francisco, where he was Music Director for six years.

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Davide Guggi

Advisor, CMC

Davide graduated as a pharmacist and received his PhD in Pharmaceutical Technology and Biotechnology from the University of Vienna. He has over 20 years of experience in the pharmaceutical industry, principally in the field of oncology. At the beginning of his career, Davide led oncology business units and commercial departments at Mundipharma and Gilead across Austria and Eastern Europe. Since over 10 years he has been working as a CMC expert, covering operational and regulatory CMC functions on behalf of over 20 different small- and medium-sized biotech companies across the world. He has served as CMC Director and CSO/CTO for several years, developing both small molecules and biologics (mABs, Fab, ADCs and Radio-immuno-conjugates) from early discovery to NDA/BLA in the US, EU and Canada, with a focus on First-in-Human and Phase I/II studies in oncology indications.

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