Why Doesn't Immunotherapy Work in Some Cancers?

Why Doesn't Immunotherapy Work in Some Cancers?

Over the past 10 years, one of the greatest revolutions in cancer treatment has been immune checkpoint inhibitors . Anti–PD-1/PD-L1, CTLA-4, and more recently LAG-3 antibodies have reactivated patients' immune systems, bringing breakthroughs in many cancers that long had few options. Durable responses in tumors such as melanoma, lung cancer and kidney cancer have generated enormous excitement in the scientific community.

The reality, however, is that these treatments do not work equally well for everyone. Clinical data show that only about one-third of patients derive long-term benefit from immunotherapy . The remainder either never respond (primary resistance) or lose their initial positive response over time (acquired resistance).

This leads to one of oncology's most critical questions: Why do these powerful immune-activating treatments fail in some patients? The answer is not merely a matter of scientific curiosity; it is vital to extending more patients' lives.

🔑 Immunologically “Hot” and “Cold” Tumors

One of the most critical factors determining immunotherapy success is how the tumor interacts with the immune system.

• Immunologically Hot Tumors: Have a high tumor mutational burden (TMB), produce many neoantigens, and show substantial T-cell infiltration within the tumor microenvironment. They therefore respond better to immunotherapy.
• Immunologically Cold Tumors: Are almost “invisible” to the immune system. They have low TMB, with T cells either absent (immune desert) or unable to enter the tumor (immune exclusion). They are therefore resistant to immunotherapy.

In brief: hot tumors activate the immune system, while cold tumors effectively hide from it.

Cancers in Which Immunotherapy Is Strong or Weak

Note: The table summarizes general patterns of immune response; individual responses may differ.

Primary Resistance (From the Outset)

Primary resistancemeans immunotherapy has no effect from the start. The patient begins treatment, but the tumor does not respond at all. This is a major obstacle seen in approximately two-thirds of patients .

Main Causes:

• Insufficient antigens: If the tumor does not produce enough “targets,” the immune system cannot detect it.
• Loss of HLA or B2M: Tumor cells remove the “cards” that would be presented to the immune system. T cells therefore cannot engage.
• WNT–β-catenin and STK11/KEAP1 mutations: These genetic changes prevent immune cells from entering the tumor, creating an “immune desert.”
• Suppression by the tumor microenvironment: The tumor creates a strongly immunosuppressive environment that inhibits T cells.
• Imbalance in gut flora: Studies in recent years show that the balance of the gut microbiota plays a critical role in immunotherapy response.

Immune Desert and Immune Exclusion:

One typical form of primary resistance is the “immune desert”: almost no T cells are present around the tumor. Another is “immune exclusion”: T cells reach the tumor's surroundings but cannot enter it. In both cases, immunotherapy “works in vain.”

Clinical Example:

STK11/KEAP1 mutations in patients with lung cancer often render PD-1 monotherapy ineffective. This group is therefore generally treated with combination therapies (such as PD-1 + CTLA-4 or PD-1 + chemotherapy).

♻️ Acquired Resistance (Developing Later)

Acquired resistanceoccurs when a tumor initially responds to immunotherapy but gradually “learns” to evade the immune system. The tumor first shrinks, then begins growing again after a while. This is one of the most disappointing situations in clinical practice.

Main Mechanisms:

• Neoantigen loss: Tumor antigens initially targeted by the immune system disappear over time. T cells can no longer recognize the tumor.
• JAK/STAT pathway disruption: Tumor cells become unable to respond to interferon signals. The immune system is then ineffective even when activated.
• Increased alternative checkpoints: Molecules such as TIM-3, LAG-3, or TIGIT become active, effectively applying the “brakes” to T cells.
• T-cell exhaustion: After prolonged fighting, T cells lose their function and become ineffective.

Clinical Clues:

• MSI-H colorectal cancer: Initially responds strongly to treatment. However, if B2M loss or JAK1/2 mutations develop over time, progression becomes inevitable.
• Melanoma: When resistance develops in patients who responded to PD-1 treatment, increased LAG-3 or T-cell exhaustion is often observed.

💡 Important Note:

Acquired resistance usually emerges within the first few years. Even after a response to immunotherapy, patients should therefore undergo regular close clinical follow-up and repeat biopsy monitoring.

Strategies for Overcoming Resistance

Approaches to overcoming immunotherapy resistance include both combinations currently in use and innovative investigational strategies .

✔️ Used in Clinical Practice:

• PD-1 + CTLA-4 combination: Standard in melanoma and non-small cell lung cancer. While PD-1 “presses the accelerator,” releasing the CTLA-4 brake activates T cells more strongly.
• PD-1 + LAG-3: Nivolumab + relatlimab has FDA approval in melanoma. It removes the LAG-3 brake that becomes active after PD-1 suppression is overcome.
• PD-1 + chemotherapy / radiotherapy: Cytotoxic treatments expose tumor antigens, allowing the immune system to see its target more clearly.
• PD-1 + VEGF inhibitor: In kidney and liver cancers, inhibiting blood vessel formation allows immune cells to enter the tumor more effectively.

🔬 Under Investigation:

• Microbiota modulation (FMT, probiotics): Healthy gut flora allows T cells to respond better to immunotherapy.
• Adenosine, TGF-β, and IDO inhibitors: Target immunosuppressive molecules in the tumor microenvironment.
• Oncolytic viruses, STING/TLR agonists: Make “cold tumors” visible to the immune system, turning them hot.
• Personalized neoantigen vaccines (mRNA): Patient-specific tumor antigens help the immune system mount a more targeted attack.

Current approaches aim to eliminate multiple mechanisms used by tumors to suppress immunity simultaneously, rather than targeting a single checkpoint.

Clinical Scenarios

Immunotherapy success varies by cancer type and the tumor's genetic and immunological characteristics. Here are some common clinical scenarios:

• NSCLC (STK11/KEAP1 mutations): These mutations make it harder for immune cells to enter the tumor. Case example: In a 60-year-old lung cancer patient, PD-1 monotherapy failed, while PD-1 + CTLA-4 or PD-1 + chemotherapy provided substantial benefit.
• Melanoma: In cases that do not respond to PD-1 treatment, a PD-1 + LAG-3 combination delays progression. Case example: Small clinical series reporting renewed responses after fecal microbiota transplantation (FMT) when progression develops during prolonged PD-1 treatment offer hope.
• MSI-H Colorectal Cancer: The group initially deriving the greatest benefit from immunotherapy. However, if B2M loss or JAK1/2 mutations develop over time, resistance emerges. Case example: After an excellent response over the first 12 months, progression was detected on a subsequent PET scan, and repeat biopsy confirmed B2M loss.
• Renal Cell Cancer: Nivolumab + ipilimumab is an effective standard treatment. However, some patients show “primary resistance.” Adding a VEGF inhibitor in this situation may improve response. Case example: In a patient resistant to immunotherapy alone, metastases shrank after a VEGF inhibitor was added.
• Head and Neck Cancer: Pembrolizumab alone benefits patients with high PD-L1. However, in patients with low PD-L1, a chemotherapy–immunotherapy combination is more effective. Case example: In a case with low PD-L1, disease progressed rapidly on immunotherapy alone; subsequent combination with chemotherapy achieved control.

These scenarios show that treatment decisions should consider tumor genetics, the immune microenvironment, and patient factors together, rather than a single biomarker.

Planned Future Studies

Researchers continue to seek new ways to overcome immunotherapy resistance. Strategies expected to change clinical practice in the coming years include:

• TIGIT inhibitors: Combined with PD-1 inhibition, they aim to release an additional “brake” on T cells. They are in phase 3 trials and are particularly promising in PD-1-refractory melanoma and lung cancer.
• Adenosine pathway inhibitors: Prevent accumulation of immunosuppressive adenosine in the tumor microenvironment, allowing T cells to reactivate. These agents aim to create a hot environment, particularly in immunologically cold tumors.
• Oncolytic viruses and STING agonists: One strategy for “igniting” cold tumors. They infect tumor cells, exposing antigens and sending a strong alarm signal to the immune system.
• Microbiota interventions: Fecal microbiota transplantation (FMT) and probiotics may improve immunotherapy success by reshaping gut flora. Following initial phase 2 results, larger phase 3 trials are planned.
• Personalized neoantigen vaccines (mRNA): mRNA-based vaccines tailored to each patient's tumor may guide the immune system like a “personal trainer.” They are being studied in combination with PD-1 inhibitors.
• The perspective from Türkiye: Clinical trial participation has increased in Türkiye in recent years. Innovative immunotherapies such as LAG-3 and TIGIT agents are currently accessible only through clinical trials , increasing the importance of participation in global research for Turkish patients.

Future immunotherapies aim to wage a combined battle against the full range of strategies tumors use to hide from immunity, rather than against a single target.

✅ Conclusion

Immunotherapies have transformed cancer treatment, offering many patients longer lives and even lasting remission. Yet not every patient shares in this success. Resistance remains one of the toughest obstacles in oncology practice.

Our strongest tools today are biomarker-based patient selection, well-designed combination therapies and careful clinical follow-up. These approaches make it possible to overcome some patterns of resistance.

In the future, interventions targeting the microbiota, next-generation checkpoint inhibitors, oncolytic viruses, and personalized neoantigen vaccines may make durable responses possible for many more patients.

In brief, although immunotherapy does not yet offer a solution for everyone, intensive research into resistance mechanisms continues to build hope in oncology.

📚 References

1. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell. 2017. [DOI Link]
2. Skoulidis F, Goldberg ME, Greenawalt DM, et al. STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma. Cancer Discovery. 2018. [DOI Link]
3. Baruch EN, Youngster I, Ben-Betzalel G, et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science. 2021. [DOI Link]