Core Framework & Diagram The Origins of Cancer Immunology
7 月 24, 2026Core Framework & Diagram The Discovery of Immune Checkpoints (A Nobel Story)
7 月 24, 2026Humanity's first attempt to kill cancer using the immune system was in 1891
——A surgeon, a bottle of bacteria, and a history almost forgotten for nearly a hundred years.
I. A surgeon's confusion, and an observation that changed history
In 1890, William Coley was a young surgeon at New York Memorial Hospital. His first sarcoma patient — a seventeen-year-old girl named Bessie Dashiell — died within months of diagnosis. This outcome left Coley unable to rest, driving him to dig through hospital archives, searching for any circumstances under which seemingly hopeless sarcoma patients had survived miraculously. After going through large numbers of records, he found one case: a male patient with an inoperable facial sarcoma who, after experiencing two severe episodes of erysipelas (a skin and soft tissue infection caused by Group A Streptococcus, causing high fever and systemic inflammation), had his tumor spontaneously regress, ultimately making a complete recovery. Coley spent considerable effort tracking down this patient and ultimately found him — a man named Fred Stein, still alive and healthy seven years after his sarcoma had regressed.
This visit was the pivotal moment for Coley's entire career shift. He began thinking about a question that almost nobody seriously entertained at the time: could the immune response triggered by bacterial infection happen to also attack tumors? In 1891, Coley took the step: he directly injected live Streptococcus into an advanced sarcoma patient's tumor. The patient developed fever, chills, and severe infection symptoms — but then, the tumor began to shrink. This was the first recorded, deliberate use of immune stimulation to treat cancer in human history.
2. Coley's Toxins: immunotherapy a hundred years early
Over subsequent decades, Coley continuously refined his method. He switched to inactivated (heat-killed) bacterial mixtures to reduce severe infection risk while preserving immune stimulation effects. This mixture typically included two bacteria: Group A Streptococcus (Streptococcus pyogenes) and Serratia marcescens, later called 'Coley's Toxins.' He used this method to treat over 1,000 patients and published numerous case reports — some osteosarcoma and soft-tissue sarcoma patients achieved complete remissions lasting multiple years. But Coley's work faced serious questions from the start. Inability to reliably reproduce effects was the core problem — highly dependent on toxin batch quality, injection site, patient baseline immune status, and whether sufficient fever had been induced. Other doctors using the same method had inconsistent results. No theoretical support was the second fatal weakness. Coley himself didn't know why bacterial infection could shrink tumors. Immunology in the 1890s was not yet a formal discipline — T cells wouldn't be discovered until the 1960s, cytokines wouldn't be conceptualized until the 1970s, NK cells wouldn't be identified until 1975.
More unfortunately, Coley lived in the era of radiation therapy's rise. Within ten years of X-rays being discovered, radiation therapy began treating cancer — visible effects, relatively clear mechanism (radiation directly damages DNA and kills rapidly dividing cells), quickly winning mainstream oncology support. After Coley died in 1936, Coley's Toxins gradually faded from clinical use. The FDA classified them as 'unproven drugs' in 1963, effectively ending their use in the United States.
3. His daughter, and a history that was rescued
If not for Coley's daughter Helen Coley Nauts, this early history of cancer immunology might truly have vanished into archive rooms. In 1953, Helen founded the Cancer Research Institute (CRI), specifically funding tumor immunology research — this institution later became an important force driving the entire field, and was an early funder of James Allison and Tasuku Honjo's research. Helen spent decades collecting and organizing the over 1,000 patient case files her father left behind, systematically analyzing the common characteristics of these cases and publishing multiple historical retrospective studies. Her work helped researchers retrospectively analyze Coley's Toxins' possible active components and preserved this period of history.
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Coley, without any theoretical tools, through clinical intuition found a correct direction: activating the immune system can let the body defeat cancer on its own. He was just a hundred years ahead of theory — and that hundred years was precisely immunology's century of creation. |
4. Modern analysis: what Coley's Toxins were probably doing
Modern analysis suggests Coley's Toxins' effects very likely came from multiple mechanism accumulation: bacterial lipopolysaccharide (LPS) and peptidoglycan activating innate immunity through TLR receptors; large amounts of cytokines (especially TNF-α) being released, directly causing hemorrhagic necrosis of tumor tissue; fever responses enhancing NK cell and CTL activity; and inflammatory environments promoting dendritic cell activation and tumor antigen presentation. Each mechanism, when viewed through modern immunology, maps to a recognized pathway that modern immunotherapy also tries to activate. Coley was using a single blunt instrument that happened to hit multiple targets simultaneously — explaining both why it sometimes worked spectacularly and why it was so unreliably reproducible. Without knowing which lever he was pulling, he couldn't control which combination he activated.
5. The long dormancy and rebirth of cancer immunology
After Coley's Toxins faded, cancer immunology didn't completely disappear — it slowly accumulated on the margins, waiting for theoretical tools and experimental technology to catch up. In 1976, BCG (Bacille Calmette-Guérin, originally a tuberculosis vaccine) was FDA-approved for treating early non-muscle-invasive bladder cancer — the first formally regulatory-approved tumor immunotherapy, and Coley's approach returning in formal drug form seventy years later. BCG's mechanism and Coley's bacterial stimulation are essentially the same: through intravesical instillation, BCG contacts the bladder mucosa, triggering strong local immune response, including large-scale activation of NK cells, T cells, and cytokines, recognizing and attacking residual tumor cells. To this day, BCG intravesical instillation remains standard treatment for early non-muscle-invasive bladder cancer, with hundreds of thousands of patients receiving this treatment annually.
The true turning point was the discovery of T cell inhibitory receptors in the 1990s. The identification of CTLA-4 and PD-1 finally provided precise molecular targets for immune activation therapy, giving 'what to use to open the immune system' a specific, manipulable concrete answer. Coley's intuition from a hundred years earlier was realized through modern molecular biology's precise tools.
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