A landmark 2026 review published in Redox Biology clearly states that the NADH/NAD+ ratio is a critical cellular "signaling switch" that directly determines cell fate and metabolic direction. Imbalance in this ratio is a core driver that disrupts the tumor microenvironment and fuels tumorigenesis and progression. This invisible life-or-death struggle is essentially a fierce competition between cancer cells and immune cells for NAD (including NAD+ and NADH)—a vital core resource. Each side has distinct needs and strategies; this battle determines not just victory or defeat, but life and death.

(Source: Redox Biology, 2026)

PART 01 Cancer Cells and Immune Cells: A Fierce Battle for NAD+

The reason tumors take root and grow in the human body is fundamentally that cancer cells, through cunning strategies, seize the core resource NAD+ and ultimately outcompete immune cells in this immune offensive-defensive war. NAD+ acts as a double-edged sword: it holds vastly different meanings for immune cells and cancer cells, making it a strategic resource fiercely contested by both sides.

1.        For Immune Cells: NAD+ Is an Indispensable "Fuel for Combat Effectiveness"

Immune cells are the body's "anti-cancer guardians." To precisely identify and efficiently eliminate cancer cells, they rely entirely on sufficient NAD+ supply. Abundant NAD+ provides powerful momentum to immune cells:

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• Activates T cells and enhances the tumor-killing capacity of CAR-T cells
• Maintains robust anti-tumor activity in M1-type macrophages
• Strengthens NK cell cytotoxicity and cytokine secretion via the SIRT1 pathway

2.        For Cancer Cells: NAD+ Is a "Secret Weapon" for Immune Evasion

Cancer’s lethality stems from its extraordinary adaptability and cunning—its ability to disguise, strengthen, and evade detection. To seize NAD+ resources and escape immune cell attacks, cancer deploys three ruthless tactics to corner immune cells:

• ·        Hyperactive Self-Production

Cancer cells highly express NAMPT, the rate-limiting enzyme in the NAD+ salvage pathway, activating a "self-sufficiency" mode to frantically synthesize NAD+ and hoard this core resource exclusively.

• ·        Immune Disguise

Cancer cells use NAD+ to sustain high expression of the PD-L1 protein—like donning an "invisibility cloak"—rendering them unrecognizable to the immune system and achieving perfect immune evasion.

• ·       Predatory Plundering

Cancer cells aggressively scavenge all NAD+ in the tumor microenvironment, leaving tumor-infiltrating lymphocytes (TILs) completely "starved." Deprived of NAD+ and energy, TILs become paralyzed and lose all anti-tumor function.

This is the cruel reality of the struggle: cancer cells’ relentless NAD+ plunder renders immune cells dysfunctional, allowing tumors to grow unchecked and gradually destroy human health.

PART 02 The NADH/NAD+ Ratio: Governing Tumor Life and Death

In the tumor microenvironment, NAD+ is a double-edged sword: supplementing it may boost immune cells’ anti-cancer power, but it could also aid cancer cells’ immune evasion and accelerate tumor growth. Which side benefits from NAD+ is not subject to human control and remains an unresolved challenge in current technology.

Simply increasing or decreasing NAD+ cannot enable immune cells to defeat cancer cells. What truly determines tumor progression is not the absolute levels of NAD+ or NADH, but the dynamic NADH/NAD+ ratio—a "bidirectional regulator" that directly controls tumor survival or demise.

1.        Decreased NADH/NAD+ Ratio: Cancer Cells Grow Uncontrollably

A lowered NADH/NAD+ ratio tips the balance in favor of tumor cells and accelerates cancer proliferation, invasion and metastasis while boosting malignancy. It accelerates lipid synthesis to support rapid cancer cell growth, raises ATP production and antioxidant capacity within tumor cells to help them evade immune surveillance. Meanwhile, it suppresses tumor-suppressive pathways including p53 and NF-κB to disrupt cellular stability, and upregulates PD-L1 expression to further facilitate immune escape, creating favorable conditions for continuous tumor progression.

2.        Elevated NADH/NAD+ Ratio: Cancer Cells Become Inactive and Perish

On the contrary, a higher NADH/NAD+ ratio restrains cancer cell activity and drives tumor cells toward natural death. It blocks energy metabolism inside tumors to restrain excessive cell proliferation, and triggers lethal reductive stress to induce cancer cell apoptosis and programmed cell death. It also increases cancer cell sensitivity to ferroptosis and activates cellular senescence pathways to halt the growth of liver cancer and other tumor types, enabling tumors to collapse gradually from the inside out.

To sum up: A moderate ratio increase may trigger tumors to collapse from within.

PART 03 Don’t Blindly Supplement NAD+—Precise Ratio Regulation Is the Key to Anti-Cancer Therapy

This NAD+ battle between cancer and immune cells reveals a critical truth: NAD+ itself is neither inherently good nor evil. Blind supplementation may backfire. The real breakthrough lies in precise regulation of the NADH/NAD+ ratio.

The ideal state is:

• Maintain an optimal NADH/NAD+ ratio in immune cells to preserve robust anti-tumor activity
• Shift cancer cells toward a high NADH/NAD+ ratio to trigger death, inhibit proliferation, and block immune evasion

This represents the cutting edge of cancer therapy: not just NAD+ supplementation, but restoring NADH/NAD+ balance—returning core resources to immune cells and leaving cancer cells in a state of terminal decline.

Reference

Li J, Zhang T, Ma T, et al. Why Is the Tumor Microenvironment Disordered by NADH/NAD+ Imbalance and How Can We Intervene?[J]. Redox Biology, 2026: 104145.