For decades, cancer has been defined by what it does: a collection of cells that grows uncontrollably and spreads to other parts of the body. This definition shaped early oncology treatments, pairing local interventions such as surgery and radiation with systemic chemotherapy to suppress cancer cell division in and beyond the primary tumor. But advances in cancer biology now tell a far more complex story.
Tumors behave less like random collections of cells and more like living, self-organizing ecosystems, earning descriptions in recent scientific literature as “transformed cells subject to evolution by natural selection,” “island-like ecosystems”, and “species-rich ecological communities”[2]. What unites these descriptions is a Darwinian shift in perspective: cancer is no longer defined by growth alone, but by dynamics within an evolving ecosystem of diverse cells shaped by natural selection and ecological interaction.
Within these ecosystems, cancer cells, immune cells, blood vessels, microbes, and structural tissues interact continuously, shaping how disease grows, spreads, and responds to therapy[1]. This ecosystem perspective is reshaping how scientists and clinicians identify cancer vulnerabilities and design future therapies.
Why Growth-Centric Thinking Falls Short
Suppressing proliferation alone cannot explain therapeutic resistance, recurrence, or metastatic evolution. Heterogeneity and selection are unavoidable consequences in an evolving ecosystem; eliminating fast-dividing cells does not eliminate the system driving the disease.
The Tumor Ecosystem: Cooperation, Competition, and Selection
Key concepts include cooperation (immune invasion, angiogenesis), competition for nutrients, oxygen, and space, and microenvironmental niches. Selective pressure imposed by therapy means resistance is not just a mutation problem, it’s an ecological outcome; treatments reshape the ecosystem, often in unintended ways.
Resistance as a Darwinian Inevitability
Cancer progression and treatment resistance follow the same basic principles as evolution by natural selection. Therapy acts as a selective pressure, favoring the survival of the most adaptable cellular states. Adaptation doesn’t depend solely on fixed genetic mutations; cancer cells can adopt different phenotypic states, often reversibly without changing their underlying DNA, allowing rapid survival under stress/therapeutic pressure. Resistance emerges even when treatment works because killing more cells can accelerate resistance; strong selection favors fit variants, whereas weak selection preserves diversity; maximal kill increases selection intensity and resistant or plastic states gain a relative advantage; the ecosystem reorganizes around survival under pressure.
Rethinking Vulnerability: From Cells to Systems
Vulnerabilities are relational, not intrinsic. Dependencies are created by the ecosystem and the fragile equilibrium within tumors. Points of coordination rather than domination suggest that disrupting coordination among cancer cells and their environment can destabilize the system. The most effective interventions may not kill the most cells, but destabilize the system that sustains them.
This means therapy design should prioritize combination and sequencing over single agents, modulating environments not just targets, using timing as a therapeutic variable, and valuing durability over maximal kill (cancer as a chronic disease). Designing therapies that manage evolution, selection and adaptation rather than aiming to eliminate it shapes the evolutionary trajectory of the tumor ecosystem.
Implications for the future of oncology
If cancer is an evolving ecosystem, then progress in oncology depends on redefining what success looks like: from eradication to durable control (stable disease may be a success; delayed resistance may be progress); from most potent therapy to most sustainable, and from maximal dose to adaptive strategy (e.g. metronomic dosing); from single agents to dynamic combinations and from siloed expertise to integrated thinking.
As our definition of cancer evolves, so too must the strategies we use to confront it, shifting attempts at domination to approaches that acknowledge, anticipate, and manage evolution itself.
The Tumor as a Self-Organizing System
A solid tumor is not made of cancer cells alone. It includes cancer stem cells that can regenerate the tumor, stromal cells that provide structural support, blood vessels that deliver nutrients, immune cells that can either attack or protect the tumor, and even resident microbes. These components evolve together over time, forming a specialized niche that supports survival and immune escape[2].
Communication inside this system is constant. Cells exchange signals through cytokines, chemokines, growth factors, matrix-remodeling enzymes, and tiny membrane-bound particles called extracellular vesicles. These signals influence how immune cells behave, how blood vessels form, and how the surrounding tissue is reshaped. The architecture that emerges from this communication often determines whether a tumor remains controlled or progresses aggressively[2, 3].
The Immune Architecture Inside Tumors
Most tumors contain many types of immune cells. These include CD8 and CD4 T cells, B cells, natural killer cells, macrophages, neutrophils, myeloid-derived suppressor cells, and regulatory T cells. Importantly, these cells are not randomly distributed. They form spatial patterns that reflect ongoing immune activity or immune suppression.
In some cancers, researchers have discovered organized immune structures known as tertiary lymphoid structures, or TLS. These resemble miniature lymph nodes that develop directly within or around tumors. They contain defined T-cell zones, B-cell zones, and germinal center-like regions where immune responses can be refined.
The presence and maturity of TLS often correlate with better patient outcomes and improved responses to immunotherapies. Their existence suggests that, under the right conditions, the immune system can organize itself inside tumors in ways that promote durable anti-cancer responses[4, 5].
The Tumor Microbiome and Stromal Support
An emerging discovery is that many tumors contain their own microbiome. These bacteria are not contaminants but residents that influence immune signaling, tumor metabolism, angiogenesis, and tissue remodeling. Different cancer types tend to harbor distinct microbial profiles, adding another layer to tumor individuality.
Alongside microbes, cancer-associated fibroblasts, endothelial cells, and perivascular stromal cells play essential roles. Together, they create physical and biochemical niches that protect cancer stem cells, regulate immune cell trafficking, and shape how nutrients and oxygen are distributed. These stromal networks often collaborate with immune cells and microbial metabolites to reinforce immune tolerance within the tumor[3].
Communication Networks and Immune Tolerance
Tumors rely on dense communication networks to maintain control over their environment. Cytokines and chemokines attract or repel immune cells. Immune checkpoint ligands suppress T-cell activation. Extracellular vesicles carry microRNAs and proteins that reprogram immune behavior at a distance. Microbiome-immune interactions further shape inflammation and tolerance.
Within this environment, certain immune populations act as tolerance hubs. Regulatory T cells, M2-polarized macrophages, myeloid-derived suppressor cells, and tolerogenic B cells concentrate inhibitory signals such as IL-10, TGF-β, and PD-L1. These signals dampen the activity of effector T cells and natural killer cells, allowing tumors to persist even in the presence of immune infiltration[1].
Where the Vulnerabilities Lie
Viewing tumors as ecosystems reveals weaknesses that are less obvious when focusing on cancer cells alone. One key vulnerability is metabolism. Tumor cells and immune cells compete for limited resources like glucose, amino acids, and oxygen. Certain immunosuppressive niches depend heavily on specific metabolic pathways or microbiome-derived metabolites. Targeting these bottlenecks can selectively weaken immune suppression while restoring immune cell fitness.
Another opportunity lies in spatial immune organization. Tumors can be broadly classified as immune-hot, immunosuppressed, immune-excluded, or immune-cold based on how immune cells are distributed. TLS density and maturity provide additional insight into these states. Therapies that remodel these architectures, by inducing TLS formation, reprogramming macrophages, or modulating the tumor microbiome, may significantly enhance the effectiveness of immune checkpoint inhibitors and other immunotherapies[2].
A New Way Forward
This ecosystem framing of cancer does not replace traditional approaches. Instead, it enriches them. By understanding tumors as living systems with internal immune architecture, metabolic dependencies, and communication networks, researchers can design therapies that disrupt cooperation rather than targeting single components in isolation.
For patients, this shift means that the future of cancer care may focus less on destroying cells indiscriminately and more on restoring balance within the immune environment. It also explains why some therapies work remarkably well in certain individuals but not others, because each tumor ecosystem is unique.
At Helix BioPharma, we believe that recognizing tumors as self-organizing immune ecosystems opens new doors for precision oncology. By studying how immune niches form, how tolerance is maintained, and where these systems are most fragile, we aim to help advance therapies that do not just attack cancer, but re-educate the environment that allows it to survive.
References:
1. Asadi M, Zafari V, Sadeghi-Mohammadi S, Shanehbandi D, Mert U, Soleimani Z, Caner A, Zarredar H. The role of tumor microenvironment and self-organization in cancer progression: Key insights for therapeutic development. Bioimpacts. 2024 Dec 7;15:30713. doi: 10.34172/bi.30713. PMID: 40256216; PMCID: PMC12008505.
2. Zhong H, Zhou S, Yin S, Qiu Y, Liu B, Yu H. Tumor microenvironment as niche constructed by cancer stem cells: Breaking the ecosystem to combat cancer. J Adv Res. 2025 May;71:279-296. doi: 10.1016/j.jare.2024.06.014. Epub 2024 Jun 10. PMID: 38866179; PMCID: PMC12126709.
3. Ciernikova S, Sevcikova A, Stevurkova V, Mego M. Tumor microbiome – an integral part of the tumor microenvironment. Front Oncol. 2022 Nov 24;12:1063100. doi: 10.3389/fonc.2022.1063100. PMID: 36505811; PMCID: PMC9730887.
4. Kyriazi AA, Karaglani M, Agelaki S, Baritaki S. Intratumoral Microbiome: Foe or Friend in Reshaping the Tumor Microenvironment Landscape? Cells. 2024 Jul 30;13(15):1279. doi: 10.3390/cells13151279. PMID: 39120310; PMCID: PMC11312414.
5. Deng S, Chen Y, Song B, Wang H, Huang S, Wu K, Chu Q. Tertiary lymphoid structures in cancer: spatiotemporal heterogeneity, immune orchestration, and translational opportunities. J Hematol Oncol. 2025 Nov 11;18(1):97. doi: 10.1186/s13045-025-01754-7. PMID: 41219991; PMCID: PMC12606831.