Background

Preface: A Hidden Threat to Urinary Health

Bladder cancer, one of the most common malignancies of the urinary system worldwide, is quietly inching its way up the ranks of global health threats. In 2022, it clocked in over 610,000 new cases globally, securing the 9th spot in the cancer hall of fame—or infamy—with over 220,000 lives lost. [1] Projections for 2040 paint a grimmer picture: deaths from bladder cancer could hit 163,000–245,000 in men and 119,000–176,000 in women. [2] In terms of diagnosis and treatment, traditional chemotherapy often leads to drug resistance in advanced patients, and immunotherapy has limited response rates. However, the advent of Antibody-Drug Conjugates (ADCs) has brought a revolutionary breakthrough in global bladder cancer treatment. In particular, enfortumab vedotin and sacituzumab govitecan have rewritten the rulebook, giving patients precious extra time.

Global mortality rate projection for 2040.

Mechanism of antibody drug conjugates (ADCs) used in urothelial cancer.

Chapter 1: Getting to Know Bladder Cancer

1. What Exactly Is Bladder Cancer?
Think of bladder cancer as a mutiny in your bladder: cells lining the organ, tired of following the rules, start multiplying like uninvited party crashers. The bladder, our body’s "urine storage unit", exposes these cells to all sorts of chemicals in urine, making them prone to rebellions (mutations). Doctors split it into two main types: Non-muscle-invasive: The rebels stay near the surface—easier to squelch, better prognosis. Muscle-invasive: The mutiny spreads deep into the bladder wall—tougher to contain, needs heavier firepower.

Diagrams of the location of bladder cancer and bladder cancer stages.

2. Who’s on Bladder Cancer’s Radar?
Smokers: Lighting up doubles to quadruples your risk. Cigarette smoke is basically a cocktail of bladder cell troublemakers. [3] Chemistry buffs (unwillingly)[4]: Workers exposed to dyes, rubber, or plastics (think benzidine) are sitting ducks. Chronic trouble: Long-term bladder infections, stones, or catheters keep cells in a bad mood, upping mutation chances. Dodgy meds: Pills with aristolochic acid? They’re like throwing gasoline on a fire for urinary cells.

1.Cigarette smoker. 2.Bladder stones. 3.Chemistry buffs. 4.Pills with aristolochic acid.

3. Warning Signs:
When Your Bladder Sends an S.O.S.
Early red flag: Painless blood in urine (like a burglar leaving a calling card without making a sound).

Blood in urine.

Late-stage chaos: Frequent urination, urgent urination, and painful urination—collectively called "bladder irritation symptoms"along with backaches or unexplained weight loss—your bladder’s way of yelling, “Help!” These often indicate advanced disease or spread..

Bladder irritation symptoms.

Unexplained weight loss

Pro tip: Blood in urine? Don’t brush it off. Bladder scopes and ultrasounds are way better than guessing games.

Bladder scope.

4.Outsmarting Bladder Cancer: Prevention 101
Quit smoking: This single move slashes risk by 70%--your lungs (and bladder) will throw a parade. Hydrate like it’s your job: Chug 2 liters of water daily. More peeing = less time for baddies to linger in your bladder. Mask up (if you must): If your job involves chemicals, gear up with gloves and respirators. Check-ups for high-risk folks: Smokers or industrial workers? Annual bladder ultrasounds could catch trouble early.

1.Quit smoking. 2.Mask up. 3.Drink plenty of water. 4.Bladder ultrasound.

Chapter 2: Bladder Cancer Treatment———
From Old School to Cutting-Edge

Clinically, bladder cancer treatment has long relied on traditional methods: "surger+ radiotherapy/chemotherapy + immunotherapy." Then, the ADCs was approved, [5]"disitamab vedotin (RC48)" was one of them, offering new hope to bladder cancer patients. It’s like a "precision missile"--composed of a "navigation system (antibody)", a "warhead (cytotoxic drug)", and a "Linker"--capable of accurately targeting cancer cells. [6] Disitamab vedotin specifically targets bladder cancer with overexpressed HER2 protein and has been designated a "breakthrough therapy" by both the U.S. FDA and China’s NMPA. Clinical trials show it can extend the survival of advanced patients with fewer side effects than traditional chemotherapy. [7]

Structure of disitamab vedotin (RC48).

Mechanism of action of RC48.

Chapter 3: The "Roadblock" for ADC Drugs: Drug Resistance

Just as bacteria "adapt" to antibiotics, cancer cells can also "resist" drugs. ADCs that once worked may become less effective or even completely useless after a period of use--this is "drug resistance." RC48 also faces this issue, which has become a major obstacle to treatment efficacy. The mechanisms of ADC resistance are not yet fully settled, but preliminary evidence categorizes them into four types: 1)Antibody-mediated resistance: Cancer cells reduce the number of HER2 proteins on their surface or alter their structure, making RC48’s "navigation system" unable to recognize them--like "changing their secret code, leaving the missile lost." 2)Impaired drug transport: After ADCs are internalized, they fail to enter lysosomes or the linker cannot break, so the "warhead" can’t be released--think of it as "the package gets stuck in the warehouse, unable to be unpacked." 3)Functional disruption: Cancer cells activate signaling pathways like Notch to enhance their survival ability, counteracting the killing effect of MMAE--"putting on a bulletproof vest to avoid bullets." 4)Payload efflux: Cancer cells "pump" MMAE out of the cell via ABC transporters, reducing its lethality--"the toxin is promptly drained, failing to deliver a fatal blow."

Complex mechanism of ADC offers multiple opportunities for resistance

Epilogue:
From Lab Benches to Hospital Beds————
Hope Marches On

——Bladder Cancer and ADCs

"In war, the way is to avoid what is strong and strike at what is weak."

—— Sun Tzu