Why Cancer Fights Back:
Cancer resistance to therapy by tissue-level homeostatic feedback | bioRxiv
Informed Prostate Cancer Support Group (IPCSG) — Member Newsletter
New Research Reveals How Your Body's Own Defenses Help Tumors Survive Treatment
Bottom Line Up Front
A major new preprint from researchers at Israel's Weizmann Institute and Technion proposes that cancer treatment resistance is not only driven by tumor mutations — it is also driven by the body's own healthy tissue-maintenance circuits fighting back. These normal "homeostatic" feedback loops, which evolved over millions of years to keep tissues stable, can inadvertently counteract drugs and allow tumors to recover. This insight, confirmed by analysis of data from thousands of cancer patients, applies to prostate cancer and seven other common malignancies. It supports emerging strategies — including treatment breaks timed to tumor biology — that could improve outcomes for men with advanced disease.
The Puzzle Every Patient Knows Too Well
If you have been living with advanced prostate cancer, you have probably experienced it firsthand: a drug works for a while, then seems to stop working. PSA levels fall, then creep back up. Your doctor switches therapies, and the process repeats. This pattern — initial response followed by relapse — is one of the most frustrating and dangerous features of advanced cancer, and it occurs across virtually every type of treatment: hormone therapy, chemotherapy, targeted drugs, and even immunotherapy.
For decades, scientists have explained this resistance through the lens of Darwinian evolution: tumors are genetically diverse, and treatment kills most cells but leaves behind rare mutant cells that happen to be resistant. Those survivors multiply, and the tumor grows back as a drug-resistant entity.
That story is real, well-documented, and important. But a striking new paper published in late March 2026 argues it is far from the whole story — and that understanding what is missing could fundamentally change how cancer is treated.
The New Research: When Healthy Tissue Saves the Tumor
The paper, titled "Cancer Resistance to Therapy by Tissue-Level Homeostatic Feedback," comes from a team at the Weizmann Institute of Science and the Technion–Israel Institute of Technology, led by Jonathan Somer, Ravid Straussman, Uri Alon, and Shie Mannor. It was posted as a preprint on March 27, 2026, meaning it has not yet completed formal peer review, though the findings draw on well-established biological principles and large validated datasets. (A preprint is a scientific manuscript shared openly before formal journal review — a now-standard first step in many research fields.)
Their central argument is captured in what they call the Homeostatic Theory of Resistance, or HTOR. In plain language: the same biological feedback circuits that keep your tissues healthy and stable can inadvertently rescue tumors from the drugs intended to kill them.
Homeostasis is your body's built-in tendency to maintain stable, healthy conditions. Think of how your blood sugar stays roughly constant even after a large meal: your pancreas releases insulin, your cells absorb glucose, and levels return to normal. The same principle applies to every tissue — your skin keeps a certain density of protective cells, your lungs maintain appropriate blood vessel coverage, your bones balance building and breakdown.
These systems rely on feedback loops: sensors detect when something is off, controllers send signals, and the system corrects itself. Engineers will recognize this as a classic "closed-loop control system." Your body has thousands of them, and they evolved over hundreds of millions of years to be extremely robust — meaning very hard to override.
The Melanoma Story: How Skin Protects Itself — and the Tumor
To illustrate their theory, the researchers built detailed mathematical models of a well-understood biological circuit: the skin's response to UV radiation. Here is how the circuit normally works:
When UV light damages skin cells (called keratinocytes), the skin needs more of the protective pigment melanin. Keratinocytes send chemical alarm signals — including molecules called IL-1 and MSH — to fibroblasts and melanocytes. Fibroblasts respond by releasing a growth factor called HGF. HGF stimulates melanocytes (the cells that produce melanin) to multiply and ramp up melanin production. More melanin means better UV protection, and the alarm signals quiet down. The circuit is back in balance.
This is elegant, robust biology. The problem? Melanoma — the most dangerous skin cancer — arises from melanocytes. BRAF inhibitors, one of the most important targeted drugs for melanoma, work by blocking an abnormal growth-promoting pathway in mutant melanocytes. In essence, BRAF inhibitors tell melanocytes to stop multiplying.
— Somer et al., bioRxiv 2026
From the skin's perspective, a BRAF inhibitor looks exactly like a problem: the melanocyte population is dropping. The skin's homeostatic circuit does exactly what it evolved to do — the fibroblasts pour out more HGF to prop up the melanocyte population. This HGF rescue signal makes melanoma cells resistant to the drug. The tumor rebounds, not because it acquired a new mutation (though that can happen too), but because the healthy tissue was doing its job.
Importantly, the researchers used real experimental data to validate the mathematical model, and their simulations matched what has been observed clinically: fibroblast-derived HGF rises after BRAF inhibitor treatment, and most patients who initially respond eventually experience disease progression, typically within five to eight months.
Blood Vessel Blockers: The Same Story in a Different Tissue
The researchers extended their analysis to a completely different class of cancer treatment: anti-angiogenic therapy. These drugs, including bevacizumab (Avastin) and related agents, block VEGF — a growth factor that tumors use to stimulate the growth of new blood vessels (angiogenesis). Cut off the blood supply, and you starve the tumor.
In practice, these drugs often produce only modest benefits, typically measured in a few months of additional progression-free survival. Resistance is common, and it frequently involves the tumor switching to other angiogenic growth factors after VEGF is blocked.
The HTOR explains this elegantly. Every cell in the body that senses low oxygen levels (hypoxia) has a built-in reflex: it activates a protein called HIF-1α and begins secreting angiogenic factors to call for more blood vessels. This is a fundamental survival mechanism. Multiple different cell types do this independently, using different signaling molecules — a design the researchers call "parallel integral feedback control." When VEGF is blocked, the system simply switches to other available channels, just as water finds a new path around a dam. Compensatory factors like FGF, angiopoietin, and ephrin rise to take VEGF's place.
No mutations required. The tissue was already wired to do exactly this.
What This Means for Prostate Cancer
While the detailed models focus on skin and blood vessels, the researchers made a critical broader claim that directly concerns prostate cancer patients: cancer cells across many cancer types preserve the cell-signaling characteristics of their healthy tissue of origin.
To test this, the team analyzed data from two massive single-cell RNA sequencing databases — the Tabula Sapiens (normal tissue samples from 15 donors spanning multiple organs) and the Curated Cancer Cell Atlas (2,836 tumor samples from 124 studies). They specifically looked at the receptor and ligand gene expression profiles — the molecular "antennas" and "broadcast signals" of cells — in both normal epithelial cells and matched cancer cells from eight organs, including prostate, breast, colon, kidney, liver, lung, ovary, and skin.
Their finding was striking. A machine-learning model trained only on normal prostate epithelial cells could identify prostate cancer cells with high accuracy — an area under the receiver operating characteristic curve (AUC) of approximately 0.93–0.96 for both receptor and ligand profiles. This means prostate cancer cells still "talk" in the same molecular language as normal prostate epithelial cells, using the same homeostatic signaling molecules they did before they became cancerous.
- ADT resistance pattern: When androgen deprivation therapy (ADT) reduces androgen-driven prostate cancer cell proliferation, the surrounding prostate stromal environment — built to support and maintain prostate epithelium — may mount compensatory signals that help cancer cells survive and adapt. This may help explain the near-universal eventual progression to castration-resistant prostate cancer (CRPC).
- Bone metastasis complexity: Prostate cancer frequently spreads to bone, and research published in 2025 in Communications Biology confirmed that the bone's stromal environment — including fibroblasts, osteoblasts, osteoclasts, and endothelial cells — creates a niche that drives treatment resistance to multiple standard therapies including darolutamide and docetaxel.
- Immunotherapy cold tumors: Prostate cancer is notoriously "cold" — resistant to immune checkpoint inhibitors. The HTOR suggests this may be partly because the prostate's normal immunosuppressive homeostatic environment is preserved in tumors, making them naturally resistant to immune attack.
- Treatment breaks and rechallenge: The HTOR offers a scientific rationale for why treatment holidays and drug rechallenge sometimes work in prostate cancer — the homeostatic rescue signals decay during the break, potentially restoring some drug sensitivity.
Putting the Pieces Together: HTOR and What Comes Before It
The HTOR does not stand alone. It is part of a growing body of research recognizing that the tumor microenvironment (TME) — the community of normal cells, immune cells, blood vessels, and structural proteins surrounding and penetrating a tumor — plays a central role in whether treatments work.
A comprehensive 2025 review published in Nature Reviews Cancer-adjacent literature confirmed that non-genetic mechanisms of resistance, including signals from cancer-associated fibroblasts (CAFs), immune cells, and the extracellular matrix, account for a substantial and previously underappreciated fraction of treatment failures. CAFs in particular — fibroblasts that have been activated by their proximity to cancer — are now recognized as major drivers of resistance in prostate cancer, secreting cytokines including IL-6, TGF-β, and CXCL12 that shield tumor cells and suppress immune responses.
A 2025 review in Frontiers in Immunology on prostate cancer specifically described how spatially organized CAF subsets build immunosuppressive niches around prostate tumors, and how treatments create selective pressure that drives "clonal-stromal co-selection" — essentially, the cancer and its stromal neighborhood adapt together in response to therapy.
Research published in Communications Biology in 2025 went a step further, creating patient-specific "microphysiological systems" — miniature lab models incorporating six different human stromal cell types from the bone metastasis environment. These models showed that the bone stromal environment independently produces resistance to both hormonal therapy and chemotherapy — confirming in a controlled experimental system what the HTOR predicts mathematically.
A New Treatment Strategy: Timing Based on Biology
Perhaps the most immediately actionable implication of the HTOR is its support for adaptive therapy — an approach that uses carefully timed treatment breaks rather than continuous maximum-dose treatment.
The conventional approach to cancer treatment is to administer maximum tolerable doses continuously, aiming to kill as many cancer cells as possible. The problem, now understood through both evolutionary and homeostatic lenses, is that continuous maximum pressure drives the fastest possible resistance. The HTOR adds an important new dimension: during those breaks, the homeostatic rescue signals that propped up the tumor have a chance to decay. When treatment resumes, the drug may work better.
A clinical trial of adaptive therapy in metastatic castration-resistant prostate cancer — using PSA levels as a guide to when to pause and restart treatment — demonstrated a roughly twofold increase in time to progression compared to continuous treatment. Mathematical modeling work published in 2025 in the Bulletin of Mathematical Biology is refining protocols to personalize adaptive therapy timing for individual patients, accounting for the substantial variation in tumor dynamics between people.
The HTOR paper explicitly notes that "timing treatments based on markers of adaptation could improve efficacy over protocols that resume treatment only upon disease progression," and states that detailed strategies for this will be developed in a forthcoming companion publication.
Many patients and oncologists are familiar with the frustrating experience of a drug working, stopping, and then — sometimes — working again after a break. This is called "rechallenge." The HTOR provides a mechanistic explanation: during continuous treatment, homeostatic feedback circuits in the surrounding tissue build up compensatory signals that override the drug. During a treatment holiday, those signals gradually decay. When the drug is reintroduced, it may face a partially "reset" microenvironment.
This does not mean rechallenge always works, or works forever — and genetic resistance mechanisms (actual mutations) also accumulate over time, which breaks and rechallenge cannot reverse. But understanding the homeostatic component may help oncologists design smarter schedules: not just when to stop, but when to restart.
A Prediction: Immune Checkpoint Resistance by the Same Logic
The HTOR team also made a specific, testable prediction that directly concerns one of the most important areas in oncology today. Immune checkpoint inhibitors — drugs like pembrolizumab that "release the brakes" on the immune system — have revolutionized treatment in many cancers, though they have had limited success in most prostate cancer patients.
The HTOR predicts that this limited success may be partly explained by homeostatic redundancy: multiple cell types in normal tissues independently sense and suppress immune activation as part of normal tissue maintenance. Block one immunosuppressive pathway (e.g., PD-1), and the homeostatic system activates compensatory immunosuppressive signals through other routes. This prediction has already been confirmed in at least one study: Koyama et al. demonstrated that T cells upregulate alternative immune checkpoints after PD-1 blockade — exactly the pattern HTOR would predict.
Important Caveats: What This Research Does Not Yet Tell Us
The HTOR is a theoretical framework, not yet a clinical protocol. The models, while grounded in real biological data, are necessarily simplifications of the extraordinary complexity of actual human tumors. Several important questions remain:
How do we measure homeostatic resistance in real patients? The theory predicts that specific biomarkers — rising HGF, compensatory angiogenic factors, increasing immunosuppressive signals — should appear before clinical progression. Developing validated tests to measure these signals in blood or tumor biopsies will be essential to applying HTOR clinically.
How do homeostatic and genetic resistance interact? The authors themselves acknowledge that the two mechanisms cooperate rather than compete. Homeostatic rescue signals may help tumor cells survive long enough to acquire resistance mutations. Separating and quantifying each component in individual patients will be complex.
Does prostate cancer have specific homeostatic circuits? The study confirmed that prostate cancer cells preserve normal prostate cell-signaling signatures, but the specific homeostatic circuits governing prostate tissue maintenance — and exactly how ADT and other prostate cancer treatments trigger them — will require dedicated investigation.
Can we safely disrupt homeostatic rescue signals? Blocking HGF, for example, could potentially prevent fibroblasts from rescuing melanoma cells from BRAF inhibitors. But HGF plays important roles in tissue repair throughout the body. The same is true of oxygen-sensing and angiogenic factors. Finding therapeutic windows that disrupt tumor-supporting homeostasis without causing unacceptable harm to normal tissue will require careful clinical work.
Looking Forward
The Homeostatic Theory of Resistance represents a genuine conceptual advance in understanding why cancer is so hard to cure. It shifts the frame from "the tumor is clever" to "the body is too robust" — and that shift matters, because it points toward different therapeutic strategies.
Rather than simply escalating drug doses or switching targets, HTOR suggests that we need to think about timing, combination strategies that include the tumor's neighborhood, and adaptive protocols that work with biological feedback rather than against it.
For men living with advanced prostate cancer — particularly those who have experienced ADT resistance, CRPC progression, or limited benefit from newer agents — this research is a reminder that the cancer's resilience is not a personal failure or simply bad luck. It reflects the extraordinary engineering of the human body, turned against itself. Understanding that engineering is the first step toward outsmarting it.
IPCSG will continue to follow this research and report on clinical trials or guideline updates that draw on these findings. As always, please discuss any questions about your own treatment with your oncologist — individual situations vary greatly, and new theoretical frameworks take time to translate into clinical practice.
Verified Sources & Formal Citations
-
Somer J, Straussman R, Alon U, Mannor S. "Cancer resistance to therapy by tissue-level homeostatic feedback." bioRxiv [Preprint]. Posted March 27, 2026. doi:10.64898/2026.03.25.714177
https://www.biorxiv.org/content/10.64898/2026.03.25.714177v1 -
The Tabula Sapiens Consortium. "The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans." Science 376, eabl4896 (2022). doi:10.1126/science.abl4896
https://www.science.org/doi/10.1126/science.abl4896 -
Tyler M, et al. "The Curated Cancer Cell Atlas provides a comprehensive characterization of tumors at single-cell resolution." Nature Cancer 6, 1088–1101 (2025). doi:10.1038/s43018-025-00897-3
https://www.nature.com/articles/s43018-025-00897-3 -
Marine J-C, Dawson S-J, Dawson MA. "Non-genetic mechanisms of therapeutic resistance in cancer." Nature Reviews Cancer 20, 743–756 (2020). doi:10.1038/s41568-020-0290-x
https://www.nature.com/articles/s41568-020-0290-x -
Straussman R, et al. "Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion." Nature 487, 500–504 (2012). doi:10.1038/nature11183
https://www.nature.com/articles/nature11183 -
Bell CC, Gilan O. "Principles and mechanisms of non-genetic resistance in cancer." British Journal of Cancer 122, 465–472 (2020). doi:10.1038/s41416-019-0648-6
https://www.nature.com/articles/s41416-019-0648-6 -
Wang L, et al. "Engineering the bone metastatic
prostate cancer niche through a microphysiological system to report
patient-specific treatment response." Communications Biology 8, Article 961 (2025). doi:10.1038/s42003-025-08384-2
https://www.nature.com/articles/s42003-025-08384-2 -
Liu X, et al. "Tumor microenvironment-mediated
immune evasion and resistance in prostate cancer: mechanisms,
cross-talk, and therapeutic opportunities." Clinical and Experimental Medicine (2025). doi:10.1007/s10238-025-01944-0
https://link.springer.com/article/10.1007/s10238-025-01944-0 -
Chen W, et al. "Tumor-immune spatiotemporal co-evolution as a paradigm for overcoming therapy resistance in advanced prostate cancer." Frontiers in Immunology 17:1797299 (2026). doi:10.3389/fimmu.2026.1797299
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1797299/full -
Zhang J, et al. (Adaptive Therapy Trial). Referenced clinical results for PSA-guided adaptive therapy in metastatic castration-resistant prostate cancer. See also: Deriving Optimal Treatment Timing for Adaptive Therapy (mathematical modeling). Bulletin of Mathematical Biology (2025). doi:10.1007/s11538-025-01525-y
https://link.springer.com/article/10.1007/s11538-025-01525-y -
Koyama S, et al. "Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints." Nature Communications 7, 10501 (2016). doi:10.1038/ncomms10501
https://www.nature.com/articles/ncomms10501 -
Bergers G, Hanahan D. "Modes of resistance to anti-angiogenic therapy." Nature Reviews Cancer 8, 592–603 (2008). doi:10.1038/nrc2442
https://www.nature.com/articles/nrc2442 -
Jain RK. "Antiangiogenesis Strategies Revisited: From Starving Tumors to Alleviating Hypoxia." Cancer Cell 26, 605–622 (2014). doi:10.1016/j.ccell.2014.10.006
https://www.cell.com/cancer-cell/fulltext/S1535-6108(14)00393-3 -
Itatani Y, Kawada K, Yamamoto T, Sakai Y. "Resistance to Anti-Angiogenic Therapy in Cancer—Alterations to Anti-VEGF Pathway." International Journal of Molecular Sciences 19, 1232 (2018). doi:10.3390/ijms19041232
https://www.mdpi.com/1422-0067/19/4/1232 -
Liang Y, et al. "Prostate cancer
microenvironment: multidimensional regulation of immune cells, vascular
system, stromal cells, and microbiota." Molecular Cancer 23, 229 (2024). doi:10.1186/s12943-024-02137-1
https://link.springer.com/article/10.1186/s12943-024-02137-1 -
Khammash MH. "Perfect adaptation in biology." Cell Systems 12, 509–521 (2021). doi:10.1016/j.cels.2021.05.020
[Foundational mathematical framework underlying HTOR]
https://www.cell.com/cell-systems/fulltext/S2405-4712(21)00194-7 -
Hanahan D, Weinberg RA. "Hallmarks of Cancer: The Next Generation." Cell 144, 646–674 (2011). doi:10.1016/j.cell.2011.02.013
https://www.cell.com/cell/fulltext/S0092-8674(11)00127-9
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