In recent years, immunotherapy—particularly immune checkpoint inhibitors such as PD-1/PD-L1 antibodies—has significantly transformed the treatment landscape for several types of cancer. However, a critical clinical question remains: Why do some patients respond exceptionally well to immunotherapy, while others see little to no benefit?

At the core of this difference lies one essential concept: Does the patient’s immune system already contain tumor-specific T cells that can be reactivated?

1. The Basis of Immunotherapy: Reactivating T Cells

Checkpoint inhibitors do not directly kill tumor cells. Instead, they release the “brakes” on cytotoxic T lymphocytes (CTLs), allowing these immune cells to recognize and destroy tumor cells more effectively. But this only works if there are already tumor-specific T cells present in the patient’s body. Without such T cells, removing the brakes does little to help—because there is no immune “engine” to move forward.

2. What Determines a Patient’s Response?

Multiple factors contribute to whether a patient benefits from immunotherapy. These include:

a. Tumor Mutational Burden (TMB) and Neoantigen Load

Cancers with high TMB, such as melanoma or lung cancer, are more likely to produce neoantigens—new antigens arising from tumor-specific mutations. These are more readily recognized by the immune system, potentially leading to stronger T cell responses.

b. T Cell Infiltration in the Tumor Microenvironment (TME)

The presence of CD8+ T cells within tumor tissue suggests that the immune system has already recognized and attempted to respond to the tumor. In these cases, immune checkpoint blockade can enhance existing responses.

c. PD-L1 Expression

Higher levels of PD-L1 on tumor cells or immune cells can indicate an "immune-active" tumor that is being suppressed by checkpoint pathways—making it more likely to respond to PD-1/PD-L1 blockade.

d. Presence of Functional Tumor-Specific T Cells

Simply having T cells in circulation is not enough. Only functionally active, tumor-specific T cells—capable of recognizing tumor antigens and secreting effector cytokines—can mediate a therapeutic response.

3. Can We Predict Who Will Respond?

This is a major goal of ongoing research. Several immune monitoring strategies are being explored, such as:

• Detecting tumor-specific T cells in blood or tumor tissue
• Profiling T cell receptor (TCR) diversity and clonal expansion
• Measuring functional T cell responses to known tumor antigens (e.g., IFN-γ secretion)

Such assessments could help clinicians identify which patients have a “primed” immune system—and are thus more likely to benefit from immunotherapy.

4. Conclusion

Immunotherapy holds great promise, but it is not universally effective. Treatment outcomes depend on multiple factors, including tumor immunogenicity, T cell activation status, and immune suppression within the tumor microenvironment. By better understanding these immune parameters—and developing accurate tools to measure them—we can move toward more personalized and effective cancer immunotherapy strategies.